The review’s central premise is that bone is not the metabolically inert scaffold it might appear to be. Its resident cells constantly make lineage decisions that determine whether the skeleton is built up or torn down, and those decisions are powered by two competing energy pathways: glycolysis, the rapid but inefficient cytoplasmic conversion of glucose to lactate, and oxidative phosphorylation, the slower but far more efficient mitochondrial route that feeds pyruvate into the tricarboxylic acid cycle. Only about 30 to 40 percent of the energy released during glucose processing is captured as adenosine triphosphate, the cell’s energy currency, so how a cell partitions flux between these pathways matters enormously. The authors contend that shifts among glycolysis, the pentose phosphate pathway, and the TCA cycle act as critical regulators of bone homeostasis, the delicate equilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts.

The story begins with bone marrow mesenchymal stem cells, the multipotent progenitors that can become either osteoblasts or fat cells. When these stem cells commit to the bone-forming lineage, their metabolism undergoes a dramatic remodel, and here the review highlights a striking species divide. In most human and rat studies, stem cells undergoing osteogenic differentiation shift their metabolic flux toward oxidative phosphorylation, with glycolytic activity falling as mitochondria take over. Mouse cells behave in the opposite manner: glycolysis is progressively enhanced during the middle and late stages of osteogenesis, eventually displacing oxidative phosphorylation as the dominant energy source. The authors stress that glycolysis and oxidative phosphorylation cooperate rather than compete, but they also flag this species discrepancy as a critical translational gap, since most mechanistic data derive from murine models while human data remain scarce.

Several molecular players emerge as master switches in this system. Mitochondrial activity elevates production of acetyl-CoA, which supplies the acetyl groups needed to acetylate β-catenin, a modification that may promote its entry into the nucleus and activation of the Wnt/β-catenin pathway, a canonical driver of bone formation. The microRNA miR-34a suppresses the glycolytic enzyme lactate dehydrogenase A, thereby dampening glycolysis and inhibiting osteogenic differentiation, while stabilizing hypoxia-inducible factor 1α upregulates glucose transporter 1 and pyruvate dehydrogenase kinase 1, boosting aerobic glycolytic flux and pushing stem cells toward the bone lineage. In aged mice, the authors note, both glycolytic capacity and oxidative phosphorylation decline in mesenchymal stem cells, a metabolic impairment that plausibly contributes to the reduced bone formation and increased marrow fat characteristic of osteoporotic bone, although whether this mechanism directly drives human disease remains unproven.

Osteoblasts, the terminally differentiated matrix-depositing cells, tell a complementary metabolic tale. Early studies established glucose as their predominant endogenous fuel, and during differentiation these cells rely heavily on glycolysis, particularly in the final mineralization stage. Glucose enters through facilitative transporters of the GLUT family, with GLUT1 mediating most uptake; deleting GLUT1 in osteoblast precursors impairs differentiation, while inactivating GLUT4 suppresses pre-osteoblast proliferation. The mechanistic target of rapamycin pathway adds another layer of control: mTORC1 acts as a metabolic brake that limits osteoblast glucose utilization, whereas mTORC2, activated downstream of the WNT-LRP5 signaling cascade via the kinase AKT, drives expression of glycolytic enzymes and enhances differentiation. Insulin and the energy sensor AMPK further modulate the picture, with AMPK activation promoting mineralization through autophagy in some studies yet upregulating the bone-formation inhibitor sclerostin in others, a reminder that metabolic regulation in bone is rarely one-directional.

Osteoclasts, the bone-resorbing counterparts, also depend intimately on glucose metabolism. When their precursors receive the RANKL signal, mitochondrial mass and oxidative phosphorylation expand to power osteoclastogenesis, but as the cells mature, glycolysis takes center stage: glucose consumption and lactate production rise, GLUT1 and glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 are upregulated, and hypoxia-inducible factor 1α, triggered by the low-oxygen environment of resorption cavities, sustains this glycolytic program. Lactate, the glycolytic end product, does double duty, maintaining redox balance, driving histone lactylation, and acidifying the local microenvironment to facilitate resorption. Transporters MCT1 and MCT2 export lactate, and blocking them with the inhibitor AZD3965 accumulates intracellular lactate, suppresses glycolytic enzymes, and inhibits osteoclast differentiation without harming osteoblasts in preclinical models, hinting at a metabolically targeted anti-resorptive therapy.

Against this backdrop, the review’s most provocative section addresses how exercise intervenes. One pathway runs through muscle-derived extracellular vesicles, tiny membrane-bound packages that contracting skeletal muscle releases into the circulation. When these vesicles are taken up by bone marrow stem cells, they deliver the glycolytic enzyme lactate dehydrogenase A, increasing glucose consumption, lactate production, and osteogenic differentiation; in mouse models of disuse osteoporosis, supplementing these vesicles restored glycolytic activity in bone tissue. Exercise intensity appears decisive, with high-intensity efforts inducing substantially greater vesicle release than moderate activity. Mechanical stress also acts directly: cyclic stretching of osteoblast-like cells increased glucose consumption, lactate, and ATP while activating the Akt/mTOR/p70S6K pathway, and fluid shear stress and vibration training promoted both glycolysis and the TCA cycle in bone cells.

Hormonal and systemic routes complete the picture. Exercise stimulates secretion of parathyroid hormone, which reshapes osteoblast metabolism by boosting glucose uptake and lactate production through IGF signaling while blocking glucose entry into the TCA cycle, a metabolic shift that underlies the hormone’s bone-building effects. Aerobic exercise upregulates PGC-1α, which in inflammatory environments shifts bone remodeling toward glycolysis-dependent bone formation and away from resorption. Resistance training raises irisin, a myokine that promotes osteoblast proliferation by enhancing glycolysis. Perhaps most strikingly, high-intensity interval training upregulates the glycolytic regulator PKM2 in endothelial cells, and the lactate they release triggers histone lactylation in bone marrow stem cells, directly activating osteogenic genes such as collagen type I alpha 2; osteoporosis patients show lower serum lactate than healthy controls, and lactate supplementation restored bone density in ovariectomized mice.

The authors are careful to temper enthusiasm with caveats. Nearly all mechanistic evidence comes from rodents or in vitro systems, no study has directly measured glucose metabolic flux in bone cells from exercising humans, and the exercise protocols used in animal models may not translate safely to frail patients at high fracture risk. Human imaging work does offer support: a study using fluorodeoxyglucose PET/CT showed that wearing a weighted vest elevated glucose uptake in the loaded limb’s muscles, cortical bone, and bone marrow, confirming that mechanical loading raises local energy demand in the musculoskeletal complex. Still, the duration, intensity, and frequency of exercise needed to achieve metabolic bone benefits in people remain unknown.

Nevertheless, the review sketches a practical horizon. The authors suggest that high-intensity interval training to boost endothelial lactate, resistance training to raise irisin, and mechanical loading to activate the PGC-1α/LDHA axis may each optimize glucose metabolism in bone, while recommending a prudent clinical default of weight-bearing aerobic exercise three to five times weekly combined with resistance training two to three times weekly, avoiding high-impact activities in established osteoporosis. Future priorities include stable isotope tracer studies to map glucose flux across species, human exercise trials tracking circulating lactate alongside bone formation markers, and cross-species metabolomics to separate universal principles from species quirks. If those efforts succeed, the humble sugar molecule may prove to be the missing link between a morning run and a fracture-free old age.

Subject of Research: The role of glucose metabolic reprogramming in how exercise attenuates osteoporosis

Article Title: The Role of Glucose Metabolic Reprogramming in Exercise-Attenuated Osteoporosis: a Narrative Review

Article References: Li, C., He, Y., Weng, K., Zhang, S., Weng, X., & Yuan, Y. (2026). The Role of Glucose Metabolic Reprogramming in Exercise-Attenuated Osteoporosis: a Narrative Review. Sports Medicine – Open, 12(1), Article 152. https://doi.org/10.1186/s40798-026-01121-x

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01121-x

Keywords: osteoporosis, exercise, glucose metabolism, glycolysis, oxidative phosphorylation, bone remodeling, osteoblasts, osteoclasts, mesenchymal stem cells, lactate, parathyroid hormone, metabolic reprogramming

The review, authored by Haoyi Song, Shao Cheng, Shang Ma and colleagues at Henan University of Chinese Medicine, synthesizes decades of evidence showing that glycolysis does far more than simply fuel bone cells. Instead, the authors propose that the glycolytic pathway operates as a genuine signaling hub, a network of enzymes and metabolites that directly instructs bone cells on how to differentiate, mature and function. This reframing matters because it suggests that the metabolic state of a bone cell is not merely a consequence of its identity but an active determinant of it, opening the door to therapies that could treat metabolic bone disease by manipulating sugar metabolism itself.

The technical story begins with glucose uptake. Bone cells express glucose transporter type 1, or Glut1, on their surface, and radiotracer studies in living mice have shown that bone takes up a striking amount of circulating glucose. Once inside, glucose is funneled through the glycolytic cascade, culminating in the conversion of pyruvate to lactate by lactate dehydrogenase, even in the presence of abundant oxygen. This phenomenon, often called aerobic glycolysis or the Warburg effect, seems wasteful at first glance because it extracts far less ATP per glucose molecule than oxidative phosphorylation would. Yet osteoblasts rely heavily on it, and genetic experiments have demonstrated that blocking glucose uptake or glycolytic flux in osteoblast precursors severely impairs bone formation.

Why would a cell that needs to build mineralized tissue choose such an inefficient energy strategy? Part of the answer lies in the biosynthetic demands of differentiation. As osteoblasts mature, they must mass-produce collagen, alkaline phosphatase and other matrix proteins, and glycolytic intermediates feed directly into the pathways that generate the building blocks for these molecules. Work on the transcription factor Runx2 has shown that glucose uptake and this master regulator of osteoblast identity synergize: glucose metabolism itself helps activate the genetic program of bone formation. Wnt signaling, a central pathway in skeletal biology, induces the Warburg effect through activation of the mTORC2 complex, and increased glycolysis has been shown to mediate the bone-forming effects of Wnt7b. In other words, the signals that tell a cell to become an osteoblast simultaneously rewire its metabolism, and that metabolic rewiring feeds back to reinforce the differentiation program.

Hypoxia adds another layer of control. The bone marrow is a surprisingly oxygen-poor environment, with direct measurements in live animals revealing very low local oxygen concentrations. Under these conditions, the hypoxia-inducible factor HIF-1α accumulates and drives the expression of glycolytic enzymes, boosting glucose consumption. In osteoblasts, HIF1α-driven glycolysis is required for normal bone formation, and activating the pathway can partially alleviate the skeletal symptoms of type 1 diabetes in experimental models. In osteoclasts, the relationship is more nuanced: HIF-1α does not appear to be essential for the differentiation of these bone-resorbing cells, but it enhances their resorptive activity, and hypoxia has been shown to increase both acid secretion and bone degradation in settings such as mandibular osteotomy.

Osteoclasts, the demolition crew of the skeleton, undergo their own dramatic metabolic shifts. Early studies dating back to the 1960s established that bone tissue metabolizes glucose aerobically, and modern work has shown that osteoclast precursors display dynamic increases in glucose metabolism at the earliest stages of differentiation induced by RANKL, the key cytokine driving osteoclastogenesis. Both aerobic glycolysis and mitochondrial respiration are required for full osteoclast differentiation, and the glycolytic enzyme lactate dehydrogenase has been shown to potentiate osteoclast formation through activation of NFATc1, the pivotal transcription factor that orchestrates the osteoclast genetic program. Pyruvate dehydrogenase kinases, which throttle the flow of pyruvate into the mitochondrial Krebs cycle, also shape osteoclast behavior; deficiency of PDK2 protects mice from ovariectomy-induced bone loss by regulating the RANKL-NFATc1 axis during osteoclast differentiation.

Perhaps the most striking findings concern glycolytic enzymes acting outside their classical metabolic roles. Pyruvate kinase M2, the embryonic isoform of the final glycolytic enzyme, can be phosphorylated by the cell adhesion molecule IgSF11, and this modification regulates osteoclast differentiation and prevents pathological bone loss in models. Phosphoglycerate kinase 1, another glycolytic enzyme, protects osteoblasts from the damaging effects of glucocorticoids such as dexamethasone by activating the NRF2 antioxidant signaling cascade when it is depleted. Aldolase, the enzyme that splits fructose-1,6-bisphosphate, physically interacts with the vacuolar H+-ATPase that osteoclasts use to acidify the resorption lacuna, directly linking sugar metabolism to the machinery of bone degradation. Even fructose-1,6-bisphosphate itself, a mid-pathway metabolite, inhibits osteoclastogenesis by attenuating RANKL-induced NF-κB and NFATc1 signaling.

Lactate, long dismissed as a metabolic waste product, has emerged as a signaling molecule in its own right. Osteoblasts express the lactate receptor GPR81 and the transporter MCT1, and lactate has been shown to induce osteoblast differentiation by stabilizing HIF1α, to enhance the bone-anabolic effect of parathyroid hormone through GPR81-PKC-Akt signaling, and to mediate the bone-building effects of high-intensity interval training. Exercise studies have demonstrated that lactate signaling through Gpr81 increases bone mass, and endothelial cell-derived lactate can trigger histone lactylation in bone marrow mesenchymal stem cells, a recently discovered epigenetic modification in which lactate-derived lactyl groups are attached to histone proteins, altering gene expression. Histone H3K18 lactylation in particular marks active enhancers, and a positive feedback loop between H3K18 lactylation and hexokinase 2 has been shown to promote bone formation in pathological settings, while exercise-induced H3K18 lactylation inhibits osteoclast activity and protects against osteoporosis.

The review also connects glycolysis to RNA modification and chromatin regulation. N6-methyladenosine, the most abundant internal chemical mark on messenger RNA, is influenced by one-carbon metabolism and glycolytic flux, and the methyltransferase METTL3 has been shown to regulate glycolysis during dental pulp stem cell differentiation and, via histone lactylation, to promote ossification by enhancing m6A methylation of BMP2 messenger RNA. Protein arginine methyltransferases add yet another dimension: PRMT6 epigenetically drives a metabolic switch from fatty acid oxidation toward glycolysis and promotes osteoclast differentiation during osteoporosis, while CARM1-mediated arginine methylation of a phosphatase regulator affects both osteogenic and osteoclastic differentiation through glucose metabolism.

The therapeutic implications are tantalizing but, as the authors are careful to emphasize, preliminary. Interfering with specific glycolytic nodes can regulate bone cell differentiation through both energy-supply and nonmetabolic signaling mechanisms, and early preclinical work is already exploring this space: bone-targeting, ROS-responsive nanoplatforms designed for precision glycolysis inhibition in postmenopausal osteoporosis, PRMT6 inhibitors that promote fracture healing by modulating osteoclast glucose metabolism, and natural compounds such as isoliquiritigenin that restore bone homeostasis by enhancing the ERK-mTOR-HIF-1α-glycolytic axis in bone marrow stromal cells. The challenge ahead is selectivity, because glycolysis is essential to virtually every cell in the body, and systemically blocking it would be catastrophic. The authors propose that targeting key nodes of the glycolytic signaling network represents a promising direction, but they stress that further in vivo and clinical studies are warranted to verify its translational value. If those studies succeed, the humble pathway that textbooks describe as simple sugar burning may become one of the most unexpected targets in the fight against osteoporosis and other diseases of the skeleton.

Subject of Research: The role of glycolysis as an energy source and signaling hub regulating osteoblast and osteoclast differentiation during bone remodeling

Article Title: Glycolysis in bone remodeling: from energy supply to signaling regulation

Article References: Song, H., Cheng, S., Ma, S., Wang, Z., Liu, B., Dan, Y., Li, J., Wei, B., Yuan, R., Wu, S., Shen, J., & Wang, S. (2026). Glycolysis in bone remodeling: from energy supply to signaling regulation. Molecular Biology Reports, 53(1), Article 1645. https://doi.org/10.1007/s11033-026-12832-5

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12832-5

Keywords: glycolysis, bone remodeling, osteoblasts, osteoclasts, lactate, HIF-1α, histone lactylation, metabolic reprogramming, osteoporosis, NFATc1, Wnt signaling, epigenetic regulation

Bone is not the static scaffold it appears to be on an X-ray. Throughout life, the skeleton undergoes continuous renewal through the coordinated activity of bone-forming osteoblasts, bone-resorbing osteoclasts, mechanosensing osteocytes, mesenchymal stem cells, immune cells and endothelial cells lining the vasculature. When this balance tips, the consequences are familiar and debilitating: osteoporosis, delayed fracture healing, and failed bone grafts. The Guangzhou team argues that ApoEVs sit at a previously underappreciated control point in this system, ferrying RNA molecules, proteins and lipids between the cell types that build and break down bone, and thereby shaping the communication networks that keep skeletal tissue in homeostasis.

Technically, ApoEVs are a heterogeneous category. The review distinguishes several subtypes based on size and biogenesis, including large apoptotic bodies, apoptotic microvesicles shed from the plasma membrane, apoptotic exosome-like vesicles, and smaller apoptotic small extracellular vesicles. What unites them is their origin in programmed cell death and their cargo: they encapsulate messenger RNAs, microRNAs, long noncoding RNAs and ribosomal RNAs, together with proteins and lipids that often reflect the identity of the parent cell. A vesicle released by a bone marrow mesenchymal stem cell carries a different molecular inventory than one shed by a mature osteoclast, and that identity matters for the message the vesicle delivers to its recipient.

Two signaling circuits dominate the review’s mechanistic analysis. The first is the RANKL/RANK/OPG axis, the central lever of osteoclast biology. RANKL, expressed on osteoblasts and osteocytes, binds RANK on osteoclast precursors and drives their differentiation into bone-resorbing giants, while osteoprotegerin acts as a decoy receptor that dampens the process. ApoEVs can modulate this axis from multiple directions, influencing the ratio of RANKL to OPG in the local microenvironment and thereby tuning how aggressively bone is broken down. The second circuit is the Wnt/β-catenin pathway, the master switch for osteoblast differentiation. When Wnt ligands engage their receptors, β-catenin accumulates and translocates to the nucleus, switching on genes such as RUNX2 and Osterix that commit stem cells to the bone-forming lineage. ApoEVs have been shown to carry Wnt pathway components and microRNAs that either amplify or suppress this cascade depending on their cargo.

The cargo story is where the biology becomes genuinely striking. In preclinical studies summarized by the review, apoptotic vesicles derived from mesenchymal stem cells delivered microRNAs that activated the AKT and ERK signaling cascades in recipient cells, promoting osteogenic differentiation marked by elevated alkaline phosphatase activity and expression of osteocalcin and bone sialoprotein. Vesicles from other sources carried insulin-like growth factor binding proteins, bone morphogenetic protein pathway components, or stanniocalcin 1, each steering recipient cells along distinct trajectories. Even the surface of the vesicle participates: the abundant phosphatidylserine on the outer leaflet of apoptotic membranes is recognized by receptors such as MerTK and TIM-4 on phagocytes, linking vesicle uptake to the same engulfment machinery that clears dying cells during normal tissue turnover.

Immune regulation emerges as a third pillar. Macrophage-derived apoptotic vesicles and T cell-derived vesicles can shift the inflammatory tone of the bone microenvironment, and the review highlights interactions with the STING pathway, a cytosolic DNA sensor that drives inflammatory signaling when activated. By modulating tumor necrosis factor alpha, interleukins and cyclooxygenase-2 signaling, ApoEVs appear to help resolve inflammation after injury, creating a permissive environment for regeneration. This osteoimmunological dimension matters clinically, because excessive inflammation is a hallmark of osteoporotic bone loss and a major obstacle to fracture healing and implant integration.

The translational implications are already being tested in animal models. In studies of critical-sized bone defects, scaffolds loaded with mesenchymal stem cell-derived ApoEVs accelerated regeneration, with the vesicles promoting both new bone formation and angiogenesis through vascular endothelial growth factor signaling. In ovariectomized rodents, the standard model of postmenopausal osteoporosis, ApoEV-based treatments improved bone microarchitecture and partially reversed the resorption-heavy imbalance. Vesicles derived from dental pulp stem cells and periodontal ligament stem cells have shown promise in periodontal and craniofacial repair, while platelet-derived and red blood cell-derived apoptotic vesicles have been explored for their regenerative and immunomodulatory properties. Mature osteoclast-derived vesicles, intriguingly, appear to feed back on osteoblasts, suggesting that even the bone-destroying cells contribute building materials to the renewal cycle.

What makes ApoEVs attractive as therapeutic vehicles is structural as much as chemical. Their lipid bilayer protects fragile RNA cargo from degradation by serum nucleases, their phosphatidylserine-rich surface promotes uptake by target cells, and their size allows them to penetrate the extracellular matrix of bone tissue. The review describes engineering strategies that exploit these properties: surface functionalization with the aspartic acid-serine-serine peptide to confer bone-targeting ability, incorporation into gelatin methacryloyl hydrogels or poly(lactic-co-glycolic acid) scaffolds for local, sustained delivery, and preconditioning of parent cells with agents such as strontium or 1,25-dihydroxyvitamin D3 to load vesicles with pro-osteogenic cargo before they are harvested.

Significant hurdles remain before ApoEVs reach the clinic. The review notes that standardization of isolation and characterization protocols is still immature, that the heterogeneity of vesicle subpopulations complicates dose definition, and that scalable production under good manufacturing practice conditions has yet to be demonstrated for skeletal applications. Questions about biodistribution, immunogenicity across donors, and the long-term fate of vesicle cargo in recipients also await rigorous answers. The authors frame these as the field’s next frontier rather than disqualifying obstacles, pointing out that the same challenges confronted and were largely resolved for the broader extracellular vesicle field now advancing through early clinical trials.

The conceptual shift, however, may prove as important as any therapy. For decades, apoptosis was taught as a one-way street ending in silent disposal. The Guangzhou review makes the case that the dying cell’s final act is communicative: it packages its regulatory contents into vesicles that instruct neighboring stem cells, immune cells and vascular cells on how to rebuild. In the skeleton, where the stakes include osteoporosis affecting hundreds of millions of people worldwide, that reframing turns cellular death from a passive endpoint into an active resource, and it positions apoptotic extracellular vesicles as candidates for a new generation of regenerative treatments built from the body’s own demolition byproducts.

Subject of Research: Roles of apoptotic extracellular vesicles in bone remodeling and regeneration

Article Title: Emerging roles of apoptotic extracellular vesicles in bone remodeling: mechanisms and applications

Article References: Wu, S., Chen, Z., Yuan, Q., Chen, H., Zhang, B., & Lin, T. (2026). Emerging roles of apoptotic extracellular vesicles in bone remodeling: mechanisms and applications. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08921-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08921-5

Keywords: apoptotic extracellular vesicles, bone remodeling, osteoporosis, bone regeneration, RANKL/RANK/OPG axis, Wnt/beta-catenin pathway, mesenchymal stem cells, osteoblasts, osteoclasts, osteoimmunology, extracellular vesicles, bone tissue engineering

The historical arc described in the editorial is striking. Reconstructive surgery in its recognizable modern form largely emerged on the battlefields of the twentieth century, where military surgeons confronted injuries of a severity and volume rarely seen in civilian practice. The demands of trench warfare in the First World War drove the development of systematic techniques for facial reconstruction, skin grafting, and the management of complex wounds, and those wartime innovations seeded the civilian specialties that followed. Over the past hundred years, the editorial notes, numerous subspecialties and branches have emerged from that foundation, some widely known and others operating in relative obscurity, but all organized around a deeply personalized approach to treating the patient.

That diversification is one of the field’s defining technical characteristics. Today the umbrella of plastic and reconstructive surgery covers procedures as different in execution as they are in purpose. At one end sit aesthetic operations such as complex facelift procedures, where the surgical goal is refinement of appearance and the technical demands center on precision dissection, preservation of vascular supply, and predictable healing. At the other end sit oncological operations, including robot-assisted tumor resection, where robotic platforms offer magnified three-dimensional visualization and instruments with articulation beyond the capability of the human wrist, allowing surgeons to work within narrow anatomical corridors while planning immediate reconstruction of the resulting defects. Between these poles lie microsurgical free tissue transfer, craniofacial reconstruction, hand surgery, burn care, lymphatic surgery, and body contouring after massive weight loss, each with its own literature, complication profiles, and technical standards.

What unites them, according to the editorial, is a shared set of goals: to improve patient quality of life through surgical excellence, to minimize complications, and to apply innovative techniques and technologies on the basis of evidence rather than fashion. That formulation matters because the field has often been caricatured as driven by cosmetic demand, when in fact its core identity is reconstructive. The same principles of tissue handling, perfusion assessment, and wound management that govern a cosmetic procedure govern the reconstruction of a mandible after cancer resection or the closure of a complex abdominal wall defect. The editorial’s emphasis on evidence-driven innovation reflects a broader movement within surgery to subject even long-standing techniques to rigorous outcomes analysis.

The new journal’s editorial stance is explicitly inclusive. It states that it will welcome research that is scientifically valid and methodologically correct, regardless of how large or small the advance. This is a deliberate departure from the traditional model in which high-profile journals prioritize novelty, accepting landmark trials and rejecting incremental studies that nonetheless contain valuable data. The argument for inclusivity rests on the mathematics of evidence. Large-scale analyses, including systematic reviews and meta-analyses, depend on the aggregation of many individual findings, and the rare complications, unusual anatomical presentations, and negative results that never reach print are precisely the data points that clinical registries and pooled analyses need most.

The editorial develops this idea through an evocative analogy: a virtual conference in which researchers share findings and engage in discussion year-round, allowing others to view a single clinical scenario from tens or even hundreds of different perspectives. Such a platform, the editorial suggests, could educate better than any textbook and generate post-hoc data of extraordinary volume. The underlying concept is familiar from other domains of medicine, where multi-institutional collaborations have revealed patterns invisible to any single center. Surgical specialties have historically lagged in this respect, partly because operative technique varies so widely between surgeons and traditions, and partly because the specialty’s global distribution means that valuable experience is scattered across institutions with vastly different resources and publication access.

Removing barriers to that participation is central to the journal’s stated mission. The editorial commits to welcoming researchers without discrimination based on novelty, location, culture, financial capacity, or surgical tradition. Open access publishing plays a practical role here: when articles are freely readable from anywhere in the world, surgeons in settings without expensive journal subscriptions can both contribute to and draw upon the shared evidence base. The editorial argues that the next stage of progress in plastic and reconstructive surgery requires a worldwide approach, in which the community gathers data and findings collectively to enable the next impactful discovery. In an era when research is easily and openly accessible from anywhere, the journal positions itself as a platform for the accumulation of evidence and knowledge rather than a gatekeeper of prestige.

The scope of the new journal is correspondingly broad. It aims to accommodate all research historically tied to plastic and reconstructive surgery as well as new and developing areas directly related to the field. The subjects associated with the launch article hint at that breadth, spanning bone remodeling and targeted bone remodeling, regenerative medicine and tissue engineering, and surgical orthopedics, alongside core plastic surgery and reconstructive surgery topics. They also include a highly contemporary clinical challenge: complications in body contouring surgery after massive weight loss, an area that has grown dramatically as the population of patients undergoing bariatric procedures and, more recently, GLP-1 receptor agonist therapy has expanded, leaving a rising number of patients with excess tissue and distinct wound-healing risks.

The intersection with regenerative medicine and tissue engineering points to where much of the field’s technical future lies. Reconstructive surgeons have long depended on transferring the patient’s own tissue, and laboratory-grown alternatives, engineered scaffolds, and biologics that modulate healing promise to extend what reconstruction can achieve when native tissue is unavailable or insufficient. Similarly, the linkage with bone remodeling reflects the growing overlap between plastic surgery and skeletal reconstruction, where understanding of how bone responds to mechanical and biological cues informs everything from craniofacial advancement to the integration of implants. These adjacent disciplines are no longer peripheral; the editorial’s framing treats them as integral to the field’s identity.

For a specialty that began with improvised repairs under battlefield conditions, the trajectory described in the editorial is a measure of how far surgical medicine has come, and of how much of its progress now depends on infrastructure beyond the operating room. The launch of a dedicated, open access, inclusively edited journal is presented not as an end in itself but as a bet that the field’s next century of advances will be built on shared, pooled, globally contributed data rather than on isolated centers of excellence. Whether that bet pays off will depend on the community the journal attracts, but the premise is clear: the diversity that made plastic and reconstructive surgery unique is now the very reason it needs a common platform on which to record, compare, and learn from everything its practitioners do.

Subject of Research: The expansion of plastic and reconstructive surgery and the role of open access, multidisciplinary evidence sharing in the field

Article Title: Plastic and reconstructive surgery: a rapidly expanding field

Article References: Sinelnikov, M. Y. (2025). Plastic and reconstructive surgery: a rapidly expanding field. BMC Plastic and Reconstructive Surgery, 1(1), Article 1. https://doi.org/10.1186/s44452-025-00004-6

Image Credits: AI Generated

DOI: 10.1186/s44452-025-00004-6

Keywords: plastic surgery, reconstructive surgery, open access publishing, robot-assisted surgery, microsurgery, regenerative medicine, tissue engineering, bone remodeling, body contouring, evidence-based surgery, craniofacial reconstruction, global data sharing

The research team, led by investigators at Tri-Service General Hospital and the National Defense Medical University in Taiwan, enrolled 43 adults with chronic low back pain who were being evaluated for suspected axial spondyloarthritis. Every participant underwent the full diagnostic workup: plain pelvic radiography, magnetic resonance imaging of the sacroiliac joints, and a whole-body positron emission tomography scan using fluorine-18 labeled sodium fluoride. Based on the combined clinical, laboratory, and imaging assessment, 29 patients were classified as having radiographic ankylosing spondylitis, 5 as having non-radiographic axial spondyloarthritis, and 9 as having degenerative joint disease, a non-inflammatory comparator group. The design was exploratory, but it was prospective and carefully standardized, with all three imaging studies completed within a two-month window.

The chemistry behind the tracer is what makes it so revealing. The fluoride ion exchanges with hydroxyl groups on the surface of newly deposited hydroxyapatite, the mineral scaffold of bone, converting it to fluoroapatite. In other words, wherever osteoblasts, the bone-forming cells, are actively laying down mineral, the tracer accumulates. Compared with older technetium-based bone agents, fluorine-18 sodium fluoride binds less to plasma proteins, reaches bone faster, and clears from the blood more quickly, producing sharper images. And because it is imaged on a PET scanner rather than a gamma camera, it delivers far better spatial resolution, standardized quantitative uptake values, and whole-body coverage in a single thirty-minute acquisition. Where MRI shows where marrow is inflamed, the fluoride signal shows how hard bone is actually responding.

The study’s primary question was whether the quantitative uptake in the sacroiliac joints, measured as the maximum standardized uptake value, or SUVmax, tracked with structural damage scored on MRI using the validated SPARCC system. It did. Sacroiliac SUVmax correlated moderately with the SPARCC structural score, with a Spearman coefficient of 0.606, and even more strongly with the SPARCC inflammation score, at 0.629, both highly significant. Because inflammation and structural damage scores were themselves correlated, the team ran partial rank correlations adjusting each association for the other, and both survived. This is the first patient-level demonstration that a single quantitative PET measure runs in parallel with both inflammatory and structural MRI domains in this disease.

The most striking finding concerned patients whose MRI showed no active inflammation at all. Bone marrow edema, the bright signal on fluid-sensitive MRI sequences that defines active sacroiliitis, was present in only 13 of the 29 ankylosing spondylitis patients. Yet visually increased fluoride uptake appeared in 23 of the 29, or 79.3 percent, including 10 of the 16 patients with no edema whatsoever. Not a single patient showed bone marrow edema without increased uptake. That asymmetry matters: it means the tracer was sensitive to disease activity that MRI classified as quiescent, consistent with the idea that bone remodeling continues even when inflammatory water signals fade. The median SUVmax in the ankylosing spondylitis group was 14.7, roughly two and a half times the values seen in either the non-radiographic or degenerative groups, which clustered around 5.5 to 5.7.

The diagnostic implications are tantalizing but come with heavy caveats. In exploratory receiver operating characteristic analyses, sacroiliac SUVmax separated ankylosing spondylitis from degenerative joint disease with an area under the curve of 0.841, and from non-radiographic disease with an area of 0.848. A threshold of 10.8 yielded 79.3 percent sensitivity and 88.9 percent specificity against degenerative disease. After bootstrap optimism correction, performance held up reasonably well, though the authors are emphatic that these thresholds were derived and tested in the same small cohort and must not be used as diagnostic cutoffs until validated externally. The non-radiographic subgroup, with only five patients, was too small for any firm conclusion, and its uptake values resembled the degenerative group’s more than the ankylosing spondylitis group’s.

Not everything the tracer lit up proved useful. Whole-body imaging revealed frequent uptake in peripheral joints and entheses, the attachment points of tendons and ligaments, across all three diagnostic groups, concentrated at mechanically loaded sites such as the feet and knees. These signals did not distinguish ankylosing spondylitis from degenerative disease, and in fact non-sacroiliac joint uptake was numerically more common in the degenerative group. Previous work in psoriatic arthritis has shown that most fluoride-positive peripheral sites are clinically silent, suggesting they reflect subclinical bone turnover rather than active inflammation. The message is clear: the whole-body scan’s real diagnostic value in this disease lies in the sacroiliac joints, not in the periphery.

Equally instructive was what did not correlate. Blood inflammatory markers, erythrocyte sedimentation rate and C-reactive protein, showed no significant relationship with sacroiliac uptake or with either SPARCC score, reinforcing a long-standing observation that systemic blood tests poorly reflect local disease in the axial skeleton. HLA-B27, the classic genetic marker, was far more prevalent in the ankylosing spondylitis group but showed no association with imaging measures within it. A single post hoc correlation between entheseal uptake and sedimentation rate failed to survive correction for multiple testing and was reported only as hypothesis-generating. Taken together, the data portray sacroiliac fluoride uptake as a measure of local osteoblastic burden, a dimension of disease that blood tests, genetics, and even MRI each capture only partially.

The study has honest limitations. The comparator groups were small, the degenerative group was defined by exclusion rather than a positive diagnostic standard, and the PET and MRI studies were not always performed concurrently because imaging occurred during routine care disrupted by the COVID-19 pandemic. Reliability of the MRI readings was not formally re-tested, and fluorine-18 sodium fluoride is fundamentally not inflammation-specific: it marks mineralization and perfusion regardless of trigger, so degenerative remodeling can mimic disease. Still, with excellent inter-reader agreement on the PET measurements, an intraclass correlation of 0.961 for SUVmax, and a biologically coherent pattern of results, the study makes a compelling case that fluoride PET/CT measures something MRI cannot see. Larger multicenter trials with concurrent imaging and validated clinical activity indices will determine whether this bone-seeking tracer earns a place beside MRI in the diagnostic arsenal, offering patients earlier and more complete answers about the disease quietly remodeling their spines.

Subject of Research: Fluorine-18 sodium fluoride PET/CT measurement of osteoblastic disease burden in axial spondyloarthritis

Article Title: ¹⁸F-sodium fluoride PET/CT as a complementary measure of osteoblastic disease burden in axial spondyloarthritis: a prospective exploratory study

Article References: ¹⁸F-sodium fluoride PET/CT as a complementary measure of osteoblastic disease burden in axial spondyloarthritis: a prospective exploratory study. (n.d.). https://doi.org/10.1007/s00259-026-08190-w

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08190-w

Keywords: ankylosing spondylitis, axial spondyloarthritis, PET/CT, fluorine-18 sodium fluoride, sacroiliac joints, MRI, SPARCC score, bone remodeling, osteoblastic activity, medical imaging, rheumatology, biomarkers

Exostoses are benign, exophytic bony outgrowths composed predominantly of cortical bone, the dense outer shell of the skeleton, though they sometimes contain cancellous bone, the spongy tissue found inside. They arise from the cortical surface of the jaws, are typically covered by normal-looking mucosa, and present as hard, painless masses on palpation. These lesions may be solitary or multiple, and their morphology can range from nodular to pedunculated, meaning attached by a stalk. Most commonly, they appear bilaterally on the buccal aspect of the maxillary alveolar ridge—the cheek side of the upper jaw’s tooth-bearing bone—while involvement of the mandible, the lower jaw, is comparatively rare. That rarity is precisely what made this young patient’s presentation noteworthy to the surgical team.

The precise cause of exostoses remains uncertain, but researchers have proposed several contributing factors. Genetic predisposition is thought to play a role, alongside environmental influences, masticatory hyperfunction—essentially, excessive chewing forces—and occlusal stress from the way the teeth meet. From a molecular perspective, bone remodeling–related genes such as RUNX2, a master regulator of osteoblastic differentiation and bone formation, have been suggested as potential contributors to abnormal bony growth patterns. Clinically, these lesions are often differentiated by location and morphology. Torus palatinus occurs along the midline of the hard palate, while torus mandibularis appears on the lingual, or tongue-facing, surface of the lower jaw, typically in the premolar to molar region. Histopathologically, however, exostoses and tori are indistinguishable: both consist of mature cortical and trabecular bone.

The epidemiology of these growths is striking. Studies report variable prevalence across populations, with torus palatinus occurring in up to 66 percent of individuals and torus mandibularis in up to 63.4 percent, while buccal exostoses have a lower prevalence of approximately 26.9 percent. Exostoses are usually asymptomatic and are most often discovered incidentally during routine dental examinations. They tend to occur more frequently in older individuals, particularly males, which makes an 18-year-old female with a solitary anterior mandibular lesion an atypical demographic on two counts. Recent studies indicate that buccal exostoses are less frequently reported than tori and predominantly occur in the posterior regions of the jaws. Anterior mandibular involvement is rare and mainly documented as isolated case reports, and the true incidence may be underestimated due to underreporting and population variability.

In this case, the patient presented to a maxillofacial surgeon with a swelling in the anterior region of her mandible that had been present for several months and had become a cosmetic concern, although it had not grown recently. Intraoral examination revealed a solitary, round, bony-hard prominence in the anterior buccal region. The overlying mucosa appeared normal, and the lesion was non-tender and immobile. There were no signs of facial asymmetry or functional impairment in speaking, chewing, or biting. The adjacent teeth were vital, with no mobility or sensitivity, and the patient had no history of parafunctional habits, trauma, or temporomandibular joint disorders. Her medical history was unremarkable, and notably, she reported no family history of exostoses—neither parent presented with similar bony protuberances—suggesting the absence of a hereditary predisposition in this instance.

Imaging played the decisive diagnostic role. The team performed a CBCT scan using a NewTom Giano HR device with a voxel size of 0.2 millimeters, a resolution fine enough to capture submillimeter anatomical detail. Multiplanar reconstructions in the axial and sagittal planes, along with three-dimensional renderings, demonstrated a well-defined, localized bony mass arising from the buccal cortex of the anterior mandible between the left central and lateral incisors. Critically, there was no evidence of invasion into adjacent structures, no root resorption, and no associated pathological changes. The differential diagnosis included buccal exostosis, osteoma, and peripheral ossifying fibroma. Correlating the imaging findings with the clinical presentation, the team established a provisional diagnosis of mandibular buccal exostosis and planned an excisional biopsy for definitive histopathological confirmation.

The choice of CBCT over conventional panoramic radiography was well justified by the physics of each modality. Panoramic radiography, the traditional first-line imaging tool for jaw lesions, is limited by magnification and distortion, with dimensional errors reported in the range of 15 to 25 percent for three-dimensional bony lesions. CBCT, by contrast, provides submillimeter accuracy of approximately 0.2 to 0.4 millimeters and eliminates the superimposition of overlapping structures, offering clearer visualization of cortical boundaries and adjacent anatomy. On CBCT, exostoses appear as well-defined cortical outgrowths with uniform density and direct continuity with the adjacent cortex, lacking internal heterogeneity, soft-tissue involvement, or expansile behavior. These quantitative advantages make CBCT considerably more reliable for assessing small anterior mandibular outgrowths that may be underestimated on panoramic images.

Distinguishing benign bone lesions from more aggressive pathologies is critical for appropriate management, and the imaging signatures differ in telling ways. Osteomas typically show higher radiodensity, a mixed cortical-cancellous pattern, and a more compact trabecular architecture; they are uncommon in the anterior mandible and occur more frequently in the paranasal sinuses. Peripheral ossifying fibroma, although primarily a soft-tissue lesion, may present with irregular internal calcifications and heterogeneous radiopacity—features absent in exostoses. Malignant tumors such as osteosarcoma and chondrosarcoma, meanwhile, often exhibit rapid growth, cortical destruction, and ill-defined margins. In this case, the lesion’s homogeneous cortical density, smooth margins, and direct cortical continuity were consistent with exostosis rather than osteoma or peripheral ossifying fibroma, guiding the team toward conservative surgical excision.

The surgery itself was performed under local anesthesia. The team raised a full-thickness triangular mucoperiosteal flap to expose the lesion, then excised the bony mass using a fissure bur and an osteotome. The surgical site was smoothed and contoured with a round carbide bur to restore continuity with the surrounding cortical bone. The excised specimen was submitted for anatomopathological examination, which confirmed the diagnosis of a benign exostosis composed of mature cortical and trabecular bone. Postoperative care included analgesics, antibiotics, and chlorhexidine mouthwash. Healing was uneventful, and follow-up visits at two weeks, three months, six months, and one year demonstrated satisfactory soft-tissue healing, preservation of the normal buccal contour, and no palpable bony irregularity at the surgical site.

The outcome carried meaningful psychological weight for the patient. Her chief concern had been cosmetic, and she reported significant improvement in self-confidence related to her facial appearance and speech after removal of the lesion. At the one-year follow-up, she reported no pain, discomfort, sensory disturbance, or functional limitation during speech, mastication, or oral hygiene procedures. The esthetic result was satisfactory, and no clinical evidence of recurrence was observed throughout the follow-up period. Because no signs or symptoms suggested complications or regrowth, the authors did not consider additional radiographic follow-up clinically necessary. The case aligns with standard management principles: exostoses are typically managed conservatively, with surgery indicated only when a lesion interferes with prosthodontic appliance placement, causes chronic mucosal ulceration, or produces esthetic or psychological concerns.

Comparisons with previously reported cases underscore just how unusual this presentation was. One earlier report documented a solitary exostosis in the right mandibular canine region that caused gingival recession around a single tooth—a contrast with the present case, where the adjacent teeth were entirely unaffected. Another described a young female with bilateral localized exostoses of the maxilla, differing in both anatomical location and lesion distribution. A third reported multiple exostoses in the anterior mandible of a 38-year-old woman, spanning the canine-to-canine region; although the anatomical site was similar, the multiplicity of lesions distinguished that case from this solitary example. In all reported cases, surgical excision was undertaken, and histopathological evaluation proved essential to confirm the benign nature of the lesions and rule out other pathologies.

The authors are candid about the limitations of their report, noting its single-center nature and inherently small sample size. The findings are descriptive and should not be interpreted as generalizable evidence; rather, the clinical observations are intended to contribute to the existing literature on rare mandibular buccal exostosis cases. Even so, the report delivers a clear message for clinicians and curious readers alike: unusual maxillofacial bone lesions demand a combination of thorough clinical assessment and appropriate imaging tools. CBCT, while not the primary diagnostic modality for such lesions, provided valuable complementary imaging that aided surgical planning and helped confirm the benign nature of the mass. For an 18-year-old worried about a lump on her jawline, that combination of careful diagnosis and precise surgery restored both her bone contour and her confidence—with no sign of the growth returning a year later.

Subject of Research: Diagnosis and surgical management of a rare anterior mandibular exostosis using cone-beam computed tomography

Article Title: Management of Anterior Mandibular Exostosis With Cone‐Beam Computed Tomography: A Rare Case Report

Article References: Abbasi, S., & Mohebiniya, M. (2026). Management of Anterior Mandibular Exostosis With Cone‐Beam Computed Tomography: A Rare Case Report. Clinical Case Reports, 14(10), Article e73565. https://doi.org/10.1002/ccr3.73565

Image Credits: AI Generated

DOI: 10.1002/ccr3.73565

Keywords: exostosis, mandible, cone-beam computed tomography, oral surgery, benign bone lesion, torus, osteoma, differential diagnosis, maxillofacial surgery, case report, dental imaging, bone remodeling

SIRT1 is one of seven mammalian sirtuins, enzymes that remove acetyl groups from histones and transcription factors in a reaction that consumes NAD+, a molecule whose abundance tracks the metabolic state of the cell. By deacetylating regulators such as FOXO, p53, and NF-κB, SIRT1 influences cell survival, senescence, mitochondrial biogenesis, and inflammatory tone. In bone, these capabilities translate into a remarkably broad portfolio. The enzyme promotes the differentiation of mesenchymal stem cells into bone-forming osteoblasts, restrains the bone-resorbing osteoclasts, and fine-tunes the signaling of osteocytes, the embedded cells that sense mechanical load and orchestrate remodeling. Because SIRT1 activity declines with age and metabolic disease, researchers have increasingly suspected that its loss contributes to osteoporosis, marrow fat accumulation, and impaired fracture repair.

The review details how SIRT1 acts on each arm of bone remodeling. In the osteoblast lineage, SIRT1 deacetylates and activates RUNX2, the master transcription factor of bone formation, and promotes the nuclear translocation of Bmi1, a polycomb protein that supports stem cell self-renewal and osteoblastic commitment. In osteoclast precursors, SIRT1 deacetylates the p65/RelA subunit of NF-κB, blunting the RANKL-driven program that produces bone-resorbing cells. In osteocytes, a CK2–USP4–SIRT1 axis stabilizes the enzyme and represses the Sost gene, lowering sclerostin output and thereby releasing the brakes on WNT/β-catenin signaling in osteoblasts. The enzyme also supports osteoblast glycolysis through regulation of GOT1, linking cellular energy metabolism directly to the bioenergetic demands of matrix synthesis and mineralization.

Bone marrow edema, by contrast, is not a single process but a spectrum. On MRI it appears as low signal on T1-weighted images and high signal on T2-weighted or STIR sequences, but the underlying histology can include interstitial fluid accumulation, fibrosis, microvascular proliferation, inflammatory infiltrates, or trabecular microdamage. The review identifies four interlocking mechanisms: vascular leakage driven by capillary dysfunction and venous congestion; microfractures from trauma or mechanical overload; inflammation that raises vascular permeability and recruits immune cells; and metabolic disturbances including hypoxia, oxidative stress, and expanded marrow fat. Rising intraosseous pressure from fluid accumulation irritates nerve endings, impairs perfusion, and produces the characteristic pain. Clinically, edema matters because it predicts cartilage wear in osteoarthritis, structural progression in inflammatory arthritis, and, in pre-collapse avascular necrosis of the femoral head, is associated with oxidative stress, fibrosis, and elevated osteoclast activity.

The critical insight of the new synthesis is that SIRT1 touches nearly every one of these mechanisms. Where direct lesion-level data are lacking, the authors assemble converging indirect evidence. SIRT1 governs the fate of bone marrow mesenchymal stem cells: when its activity falls, lineage commitment shifts away from osteogenesis and toward adipogenesis, expanding bone marrow adipose tissue. Marrow fat, in turn, is mechanistically linked to edema because it compresses vascular spaces, impairs perfusion, and secretes adipokines with proinflammatory and anti-osteogenic effects. In mouse models of chronic energy deficit, SIRT1 deficiency produces increased marrow adiposity and bone loss, and the SIRT1 activator resveratrol partially rescues these phenotypes, tying energy state, enzyme activity, and marrow composition into a single pathway.

Vascular biology offers another plausible route. SIRT1 deacetylates endothelial nitric oxide synthase, boosting nitric oxide production that maintains vasodilation and limits permeability. Loss of SIRT1 activity in mice degrades the endothelial glycocalyx, the protective proteoglycan layer lining blood vessels, while elevating superoxide production and acetylated NF-κB/p65, changes that favor capillary leakage. In bone marrow endothelial cells specifically, erythropoietin has been shown to induce nuclear translocation of SIRT1, preserving endothelial integrity through mitochondrial health. Because vascular leakage is a hallmark of marrow edema, these findings suggest that diminished SIRT1 could directly weaken the barrier that keeps fluid inside vessels.

Inflammation and oxidative stress provide a third axis. SIRT1 suppresses transcription of IL-1β, IL-6, and TNF-α by deacetylating NF-κB components, and it enhances antioxidant defenses through Nrf2, PGC-1α, and FOXO transcription factors, raising enzymes such as SOD, catalase, and HO-1. In mesenchymal stem cells, the microRNA miR-128-3p reduces SIRT1 expression and thereby increases inflammatory mediators, an effect that resveratrol can ameliorate. The enzyme also intersects with hypoxia signaling, regulating HIF-1α stability and potentially modulating VEGF-driven angiogenesis and permeability in the poorly perfused, high-pressure marrow regions where edema develops. Metabolic resilience completes the picture: SIRT1 supports mitochondrial biogenesis, glycolytic flexibility, AMPK activation, and autophagy, all of which help marrow stromal and endothelial cells maintain ion gradients and fluid homeostasis under stress.

The authors are careful to flag the limits of this framework. No published study has yet measured SIRT1 expression or enzymatic activity inside human or animal edema lesions, and causality remains unproven: altered SIRT1 could be a downstream consequence of hypoxia and inflammation rather than the initiating driver. The energy-deficit models that dominate the literature capture chronic metabolic stress but do not reproduce the acute vascular leakage and trauma-related microdamage typical of many clinical edema syndromes. Human data correlating marrow SIRT1 activity with edema severity on MRI are essentially absent. The review also notes that BME etiologies are heterogeneous, spanning trauma, osteoarthritis, ischemia, and inflammatory disease, so SIRT1’s relevance may vary by context.

Therapeutically, the stakes are considerable. Resveratrol improves trabecular bone structure in ovariectomized rodents and increases SIRT1 expression in mesenchymal stem cells from patients with type 2 diabetes, while NAD+ precursors such as nicotinamide mononucleotide and nicotinamide riboside improve endothelial function and reduce oxidative stress in other tissues. Combination strategies pairing SIRT1 activators with anti-inflammatory cytokine inhibitors or vascular-stabilizing agents have shown additive protection in analogous models, though none has been tested in edema specifically. Caution is warranted: high-dose resveratrol has in some settings reduced trabecular bone volume or increased resorption markers, resveratrol’s poor bioavailability demands novel delivery systems such as nanoparticles or bone-targeting conjugates, and systemic SIRT1 activation carries off-target risks. Spectral computed tomography, with virtual non-calcium imaging achieving sensitivities of roughly 86 to 94 percent, may soon make edema quantification faster and more accessible than MRI, opening the door to imaging-molecular correlation studies.

The review closes with a research roadmap: biopsy MRI-confirmed edema lesions to quantify SIRT1 activity; build animal models that faithfully reproduce vascular and inflammatory edema and manipulate Sirt1 genetically; run longitudinal imaging time courses to determine whether early activation prevents edema or later activation accelerates resolution; and dissect how sclerostin upregulation, marrow fat expansion, and altered stem cell metabolism converge to raise intraosseous pressure. Until those experiments are done, SIRT1 remains what the authors call a biologically plausible but unvalidated mediator, a promising molecular handle on a condition that has so far been defined only by what it looks like on a scan.

Subject of Research: The role of the NAD+-dependent deacetylase SIRT1 in bone marrow edema and bone remodeling

Article Title: The Role of SIRT1 in Mediating Bone Marrow Edema and Its Interface With Bone Remodeling

Article References: Chen, Y., Li, X., Zheng, Z., Liu, Z., Xu, T., & Tang, Y. (2026). The Role of SIRT1 in Mediating Bone Marrow Edema and Its Interface With Bone Remodeling. Immunity, Inflammation and Disease, 14(9), Article e70505. https://doi.org/10.1002/iid3.70505

Image Credits: AI Generated

DOI: 10.1002/iid3.70505

Keywords: SIRT1, bone marrow edema, bone remodeling, osteoblasts, osteoclasts, mesenchymal stem cells, marrow adiposity, NF-kB, oxidative stress, vascular permeability, resveratrol, MRI

The motivation comes from a decade of accumulating evidence on the gut–bone axis. Germ-free animals, antibiotic-treated animals, and recipients of fecal microbiota transplants all show measurable changes in bone mineral density and osteoclast activity, and Mendelian randomization studies have hinted at causal links between particular microbial taxa and osteoporosis traits. Microbial metabolites are widely viewed as the chemical messengers of this axis: short-chain fatty acids such as butyrate can rebalance regulatory and inflammatory T cell populations and even prompt bone marrow CD8-positive T cells to secrete Wnt10b, directly stimulating bone formation, while tryptophan derivatives can activate the aryl hydrocarbon receptor and shore up the intestinal barrier. What has been missing, the authors contend, is a systematic way to connect these metabolites to concrete host signaling molecules without losing track of which microbe and which substrate produced them.

To build that bridge, the team first compiled 251 gut microbiota-related metabolites and 238 human intestinal host targets from the gutMGene database, which curates literature-derived associations between microbes, their substrates, their metabolites, and human genes. Metabolite structures were retrieved from PubChem as standardized SMILES strings and submitted to two target-prediction platforms, the Similarity Ensemble Approach and SwissTargetPrediction, producing a deduplicated set of 1,518 candidate human protein targets. In parallel, osteoporosis-related genes were harvested from three disease databases, CTD, GeneCards, and OMIM, yielding 2,213 unique disease-associated targets. Intersecting the three lists produced 48 shared targets, a number that proved robust in sensitivity analyses using stricter prediction-confidence filters and higher GeneCards relevance-score cutoffs.

The 48 shared proteins were then mapped onto a protein–protein interaction network built with STRING at medium confidence, revealing 540 interactions. Five genes stood out as the most connected candidate hubs: TP53, with the highest node degree of 41, followed by IL6, AKT1, and TNF at 40 connections each, and IL1B at 39. Crucially, the authors resisted the temptation to crown a single master regulator. When they computed complementary topology measures, IL1B showed the highest betweenness centrality, while TP53 led on closeness and eigenvector centrality, and AKT1 remained highly connected without ranking first on any single metric. The team accordingly retained all five as candidate hubs for downstream analysis rather than as proven central mediators.

Functional enrichment analyses gave the shared target set a recognizable biological identity. Gene Ontology terms pointed to responses to molecules of bacterial origin, lipopolysaccharide, biotic and xenobiotic stimuli, and regulation of apoptotic signaling, alongside molecular functions involving histone deacetylase activity and MAP kinase activity. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted Toll-like receptor, IL-17, TNF, NOD-like receptor, MAPK, and PI3K-Akt signaling, as well as osteoclast differentiation and apoptosis. The inflammatory flavor of these results fits established bone biology: TNF-alpha amplifies osteoclast precursor differentiation, IL-1beta induces stromal RANKL expression, and IL-6 promotes osteocyte-mediated osteoclast formation, while all three cytokines can suppress osteogenic markers such as RUNX2 and shift remodeling toward resorption.

The centerpiece of the study is the edge-level M-S-M-T network itself, which arranges four node layers, 64 gut microbiota, 22 substrates, 30 metabolites, and the five candidate hub targets, connected by 150 edges. Enumerating directed routes from microbe to substrate to metabolite to hub yielded 479 candidate four-layer paths, with AKT1 reachable through 225 of them, IL1B through 101, TP53 through 60, TNF through 53, and IL6 through 40. The authors are explicit that this count reflects graph-theoretical connectivity in a many-to-many network, not 479 independently validated causal chains, and that records lacking a reported substrate were retained through a single placeholder node used only for visualization. Within the network, two interpretable modules emerged. Records for Clostridium sporogenes linked the amino acid tryptophan to 3-indolepropionic acid and indole-3-lactic acid, both of which were connected to AKT1. Records for Bacteroides sp. 45 supported flavonoid branches in which quercitrin connects to quercetin and hydroxyquercitrin, and rutin to isoquercetin, with endpoints at AKT1, TNF, and IL6.

To probe the plausibility of these candidate links at the structural level, the team docked three representative metabolites, 3-indolepropionic acid, indole-3-lactic acid, and quercetin, into the AKT1 crystal structure. All three produced energetically favorable poses, with quercetin achieving the most favorable score at minus 9.6 kcal/mol, followed by indole-3-lactic acid at minus 8.0 and 3-indolepropionic acid at minus 7.8. Preliminary ADMET profiling of eleven representative metabolites showed that all satisfied the conventional Lipinski rule-of-five criteria, but the toxicity predictions were heterogeneous, with several compounds, quercetin among them, flagged for elevated hepatotoxicity or carcinogenicity-related endpoints. The researchers stress that docking scores demonstrate only qualitative structural plausibility and that physicochemical criteria designed for oral drugs should not be read as evidence of therapeutic suitability for endogenous, diet-derived molecules.

The most striking external evidence came from three independent human transcriptomic datasets that played no role in building the network. In age-matched bone marrow mesenchymal stem cells from donors with primary osteoporosis, AKT1 was strongly upregulated with a log2 fold-change of 1.59 and a genome-wide false-discovery rate of 0.0099, and TP53 was likewise significantly elevated at a log2 fold-change of 1.55 and an FDR of 0.037, with TNF showing a nominally significant increase. Yet the same five hubs showed weak or inconsistent changes in circulating monocytes from postmenopausal women with low versus high bone mineral density, and no hub reached even nominal significance in circulating B cells. Fisher-combined P values across the three datasets were significant for AKT1 and TP53 but not for the inflammatory cytokine genes, pointing to a cell-type-specific transcriptional perturbation in bone-lineage cells rather than a systemic signal detectable in peripheral blood.

The authors frame the work deliberately as hypothesis-generating rather than confirmatory. Database coverage and publication frequency can inflate the prominence of well-studied genes such as AKT1 and TP53, pathway enrichment alone does not establish osteoporosis specificity, and the transcriptomic validation was confined to steady-state mRNA in three microarray datasets. No cellular perturbation experiments, protein-level measurements, animal models, or prospective clinical samples were available, and docking was limited to a single receptor and three ligands without molecular dynamics or biochemical binding assays. The value of the framework, they argue, lies in converting a vast database-derived network into a small number of testable modules, most notably the Clostridium sporogenes–tryptophan–indole metabolite–AKT1 axis and the Bacteroides sp. 45 flavonoid module, each anchored by convergent expression evidence in the right cell type.

If those modules withstand experimental scrutiny, the implications could extend well beyond osteoporosis research. A provenance-preserving network of this kind offers a template for studying how microbial chemistry reaches any host organ, and it suggests that interventions targeting the gut, whether through diet, probiotics, or metabolite supplementation, might eventually be rationally matched to molecular targets in bone. For now, AKT1 stands as one candidate signal-integration hub among several, not the unique center of the gut–bone axis, and the pathway from a Clostridium cell in the intestinal lumen to a mesenchymal stem cell in the marrow remains a hypothesis waiting for the laboratory tests that must now follow.

Subject of Research: Computational mapping of links between gut microbiota-derived metabolites and osteoporosis through a microbiota–substrate–metabolite–target network centered on candidate hub AKT1

Article Title: A microbiota–substrate–metabolite–target network suggests AKT1-associated links between gut microbiota-derived metabolites and osteoporosis

Article References: Zeng, W., Gong, Y., Liao, Y., Xie, X., Qin, Z., Li, C., & Zhang, X. (2026). A microbiota–substrate–metabolite–target network suggests AKT1-associated links between gut microbiota-derived metabolites and osteoporosis. International Microbiology. https://doi.org/10.1007/s10123-026-00899-w

Image Credits: AI Generated

DOI: 10.1007/s10123-026-00899-w

Keywords: gut microbiota, osteoporosis, gut–bone axis, AKT1, microbial metabolites, tryptophan metabolites, flavonoids, quercetin, molecular docking, network pharmacology, bone remodeling, transcriptomic validation

The central actor in this story is the senescence-associated secretory phenotype, or SASP. Senescent cells are not simply dormant; they secrete a cocktail of pro-inflammatory cytokines, chemokines, matrix metalloproteinases and growth factors. In the ageing bone microenvironment, this secretion comes from a surprising range of cell types. Senescent osteocytes, the mechanosensing cells entombed in mineralised matrix, senescent mesenchymal stem cells that would otherwise generate new osteoblasts, senescent osteoblasts themselves, immune cells resident in the marrow, and vascular endothelial cells lining the bone’s rich blood supply all contribute to the SASP. The result is a persistent, locally generated inflammatory input that remoulds skeletal biology from within.

What makes the review’s argument distinctive is its claim about convergence. The SASP is not a separate pathway running in parallel to the classical causes of osteoporosis. Instead, the factors released by senescent cells feed directly into the same signalling axes that estrogen deficiency, glucocorticoid excess and mechanical unloading exploit. These include the RANKL/OPG axis, which governs osteoclast formation and bone resorption; the Wnt/β-catenin pathway, which drives osteoblast differentiation and bone formation; and the NF-κB signalling network, the master regulator of inflammation. By flowing into these well-characterised channels, senescence amplifies resorption while suppressing formation, adding an accelerating force to mechanisms clinicians already recognise.

The molecular detail is striking. SASP cytokines such as interleukin-6, working through its soluble receptor, can potentiate RANKL-induced osteoclast differentiation via NF-κB, ERK and JNK signalling. Chemokines like CCL2 recruit inflammatory cells into the marrow, while CCL3 has been shown to cause bone loss and marrow adiposity in aged mice. SASP components also include Wnt antagonists such as sclerostin, which binds the LRP5/6 co-receptors and blocks the canonical Wnt signal that osteoblasts need to build bone. Sclerostin additionally stimulates osteocyte support of osteoclast activity through a RANKL-dependent pathway, meaning a single SASP constituent can simultaneously dampen formation and promote resorption. Osteocytes, long appreciated as endocrine cells and master orchestrators of remodelling, sit at the centre of this regulatory web, expressing RANKL and controlling both sides of the remodelling cycle.

The regulation of the SASP itself is equally intricate. NF-κB not only mediates the downstream effects of SASP factors but also drives the secretory programme within senescent cells. The inflammasome coordinates paracrine senescence, allowing senescent cells to spread their state to healthy neighbours. mTOR signalling promotes the translation of interleukin-1 alpha, a keystone of the pro-tumorigenic SASP, while p38 MAPK regulates the phenotype independently of the canonical DNA damage response. More recently, cGAS-STING signalling, triggered by leaking DNA in senescent cells, has emerged as an amplifier of the ageing process through remodelling of immune function. Epigenetic changes add another layer of control, and extracellular vesicles, tiny membrane-bound packages, have been identified as key carriers that ferry SASP cargo between cells, spreading senescence paracrinally through the marrow and beyond.

Different skeletal cell types contribute distinct SASP profiles. In osteoprogenitors expressing the transcription factor Osx1, DNA damage and senescence deplete the pool of cells available to form bone with age. Senescent mesenchymal stromal cells shift toward adipogenesis, contributing to the fatty marrow that accumulates with ageing and obesity and further impairing both blood cell and bone regeneration. Osteocyte senescence has been documented in type 2 diabetes, where accelerated senescence of these matrix-embedded cells is associated with skeletal fragility, and radiation has been shown to induce a primary osteocyte senescence phenotype that alters mesenchymal stem cell differentiation through paracrine signalling. Senescent osteocytes also undergo biophysical stiffening, potentially compromising their mechanosensing function. Even osteoclasts display a protective role in this landscape, shielding bone blood vessels from senescence through the angiogenin/plexin-B2 axis, a reminder that the senescence story is not uniformly destructive.

The review carefully distinguishes how senescence participates in age-related, postmenopausal and secondary osteoporosis. In natural ageing, senescent cell burden accumulates gradually and contributes to the slow deterioration of bone mass and microarchitecture, including de novo intracortical remodelling and porosity. In postmenopausal osteoporosis, estrogen deficiency and senescence operate as partly independent inputs; studies in young adult mice and older humans indicate that neither fully explains the other, yet both converge on the same oxidative stress and NF-κB-dependent mechanisms. In secondary forms, the evidence is particularly vivid. Glucocorticoid-induced bone loss can be prevented in mice by targeting cellular senescence through modulation of the DPP4-GLP-1 axis. Radiation-induced osteoporosis is driven specifically by p21-positive, rather than p16-positive, senescent cells, and clearing p21-high cells prevents both bone loss and marrow adiposity. Chemotherapy drives senescence in adipo-lineage cells that then promote bone loss, although one 2025 study found senolytics did not prevent chemotherapy’s adverse skeletal effects, underscoring that the picture remains nuanced.

It is the therapeutic implications that give the review its urgency. When senescent cells were cleared in aged mice, either genetically or pharmacologically, age-related bone loss was prevented, providing proof of concept that the SASP is a distinct and independently addressable contributor to skeletal ageing. Senolytic drugs such as the dasatinib and quercetin combination, discovered by exploiting the survival dependencies of senescent cells, have since shown benefit in multiple preclinical models, including postmenopausal, glucocorticoid-induced, diabetic, hypoxia-associated and vitamin D insufficiency-related bone loss. Intermittent senolytic treatment has also been reported to improve responsiveness to mechanical loading in the skeletons of aged mice, linking senescence clearance to the well-known anabolic effects of exercise. A phase 2 randomised controlled trial has now tested intermittent senolytic therapy on bone metabolism in postmenopausal women, marking a critical step toward clinical translation.

Delivery remains a central challenge, and the field is responding with engineering ingenuity. Bone-targeted nanoparticles and nanomaterials are being developed to concentrate senolytics and other therapeutics in the skeleton, and liposomal senolytic formulations have alleviated senescence-induced bone loss in preclinical work. Apoptotic vesicle-mediated senolytic approaches have been shown to require mechanical loading, suggesting that drug therapy and physical activity may need to be combined. Alternative senomorphic strategies aim not to kill senescent cells but to quiet their secretions. JAK inhibition has been shown to alleviate the SASP and frailty in old age, rapamycin extends lifespan in mice partly through mTOR modulation, and glutaminolysis inhibition achieves senolysis through metabolic vulnerability. Rejuvenating senescent bone marrow stromal cells by enhancing TFEB-mediated autophagy has alleviated age-related bone loss in middle-aged mice, and metformin’s effects on bone metabolism are under active investigation.

The authors are candid about the gaps. Senolytics and senomorphics must be evaluated against established osteoporosis treatments, from bisphosphonates and denosumab to the anabolic agents teriparatide and romosozumab, which themselves reshape the RANKL/OPG and Wnt pathways. Denosumab discontinuation causes rebound bone turnover that requires careful sequencing strategies, and the same scrutiny of long-term skeletal outcomes must be applied to senescence-targeted approaches. Biomarker validation is a priority: proteomic atlases of senescence-associated secretomes are enabling the development of circulating biomarkers, and emerging techniques such as spatial transcriptomics are mapping where senescent cells reside within bone tissue. The review also highlights that p16-positive and p21-positive cells represent distinct senotypes with different functional consequences, meaning precision may matter when targeting them. As the population ages and osteoporosis imposes an ever-heavier burden of fragility fractures, the convergence of senescence biology with classical skeletal physiology offers a genuinely new therapeutic frontier, one where ridding bone of its zombie cells, or silencing their inflammatory chorus, could preserve skeletal strength deep into old age.

Subject of Research: Cellular senescence and the senescence-associated secretory phenotype in skeletal ageing and osteoporosis

Article Title: Cellular senescence and the SASP in skeletal ageing: convergent mechanisms of progressive bone loss in osteoporosis

Article References: Liu, H., & Lei, B. (2026). Cellular senescence and the SASP in skeletal ageing: convergent mechanisms of progressive bone loss in osteoporosis. Biogerontology, 27(5), Article 164. https://doi.org/10.1007/s10522-026-10508-y

Image Credits: AI Generated

DOI: 10.1007/s10522-026-10508-y

Keywords: cellular senescence, SASP, osteoporosis, skeletal ageing, senolytics, senomorphics, osteocytes, inflammaging, RANKL/OPG, Wnt signalling, bone remodeling, senescence biomarkers