The primary cilium, a solitary, antenna-like projection found on nearly every mammalian cell, has emerged as a crucial sensory organelle responsible for detecting extracellular mechanical and chemical signals. In the context of bone biology, the functionality of primary cilia has remained enigmatic, particularly in preosteoclasts, the precursor cells to osteoclasts responsible for bone resorption. This new study presents compelling evidence that exercise triggers mechanosensitive responses in these cells via their primary cilia, promoting a local microenvironment conducive to periosteal bone accretion.

Delving deeper into the molecular cascade, the researchers demonstrated that mechanical loading from exercise stimulates the elongation and activation of primary cilia on preosteoclasts. This morphological transformation enhances the cells’ ability to sense biomechanical cues, triggering intracellular signaling pathways that modulate gene expression relevant to bone remodeling. Notably, the activation of these cilia leads to the secretion of osteogenic factors that directly facilitate periosteal bone formation, suggesting an autocrine and paracrine communication network within the bone niche.

This study employed advanced imaging techniques, including high-resolution confocal microscopy and live-cell imaging, to visualize primary cilium dynamics in response to mechanical stimuli. The dynamically elongated cilia serve as mechanotransducers, converting biomechanical inputs into biochemical signals that engage downstream effectors, including calcium influx channels and Hedgehog signaling pathways. Such mechanotransduction underscores the intimate relationship between physical activity and bone homeostasis, providing a refined understanding of how mechanical forces optimize skeletal strength and integrity.

The researchers further conducted loss-of-function experiments by genetically ablating or impairing primary cilium formation specifically in preosteoclasts, revealing a significant attenuation of exercise-induced periosteal bone growth. These findings unequivocally establish primary cilia as indispensable mediators in the mechanical regulation of bone formation, specifically within the periosteal compartment, which is critical for cortical bone thickening and overall skeletal robustness.

Moreover, the study investigated the downstream effectors of cilia-mediated signaling, identifying key molecular players, such as the polycystin complex and specific transcription factors that modulate osteogenic gene expression. Exercise-induced activation of these pathways in preosteoclasts appears to foster a favorable balance between bone resorption and formation, tilting the scale towards anabolic processes that reinforce the periosteum — the outer fibrous layer essential for bone strength and repair.

This novel insight into preosteoclast function challenges previous dogma that primarily linked osteoblasts and osteocytes as the main responders to mechanical stimuli in bone remodeling. The role of preosteoclasts, traditionally seen as precursors to bone-resorbing osteoclasts, is now redefined as active regulators of periosteal bone formation through ciliary mechanosensing. Such a paradigm shift opens new avenues for targeting preosteoclast cilia to potentiate skeletal resilience, especially in aged or osteoporotic populations where bone fragility is a major concern.

Importantly, the researchers correlated their cellular and molecular findings with in vivo models of exercise, confirming that mechanical loading through controlled physical activity robustly enhances periosteal bone accrual dependent on intact primary cilia function. These in vivo validations accentuate the translational potential of manipulating cilia-mediated mechanotransduction pathways as a therapeutic strategy to mimic the beneficial effects of exercise in bone tissue.

In terms of clinical applications, the elucidation of exercise-stimulated primary cilia function on preosteoclasts heralds promising implications for developing targeted pharmacological agents that can activate or sensitize these mechanosensors. Such agents could potentially serve as adjunctive therapies for patients unable to perform adequate physical activity due to injury, illness, or aging, thereby preserving or enhancing bone mass and reducing fracture risk.

The intersection of mechanobiology and skeletal physiology, as highlighted by this study, reflects a broader trend in biomedical research emphasizing the importance of physical forces in cellular function and tissue regeneration. Understanding how diverse bone cell populations transcend their classical roles to integrate mechanical cues enriches our knowledge of skeletal biology and may revolutionize treatment paradigms for musculoskeletal disorders.

Given the complexity of bone remodeling, which requires the coordinated interplay among osteoblasts, osteoclasts, osteocytes, and now preosteoclasts, the identification of primary cilia on preosteoclasts as mechanosensors adds a critical piece to the puzzle. This refined understanding emphasizes the necessity for a holistic approach when designing interventions aimed at improving bone health, considering the intricate cellular crosstalk influenced by mechanical stimuli.

The temporal dynamics of cilia activation and periosteal bone formation revealed by this research also suggest that the timing and intensity of exercise regimens could be optimized to maximize bone anabolic responses. Personalized exercise prescriptions based on mechanotransduction insights might emerge as a future avenue for maximizing skeletal benefits while minimizing injury risk.

Furthermore, this discovery invites an exploration of primary cilia function beyond bone tissue, potentially uncovering similar mechanosensory roles in other mechanically active tissues such as cartilage, muscle, and vascular endothelium. The expanding relevance of cilia-mediated signaling mechanisms underscores a fundamental biological principle linking physical forces to tissue homeostasis across organ systems.

As the field moves forward, integrating multi-omics approaches, mechanobiology, and in vivo imaging will be crucial to unravel the intricate signaling networks governed by primary cilia on various cell types. The therapeutic exploitation of these pathways holds immense promise, particularly in aging populations where maintaining bone strength is imperative for mobility and quality of life.

In conclusion, the revelation that exercise-stimulated primary cilia on preosteoclasts promote periosteal bone formation is a scientific milestone that redefines our understanding of skeletal mechanobiology. This seminal work by Kim JM, Lee YS, Kim MJ, and colleagues not only advances bone biology but also opens innovative prospects for combating bone degenerative diseases through biomechanically informed therapeutic interventions. The marriage of cellular mechanosensing with exercise physiology marks a new frontier in biomedical research, poised to generate impactful health solutions for an aging global population.

Subject of Research: Mechanical regulation of periosteal bone formation through primary cilia on preosteoclasts induced by exercise.

Article Title: Exercise-stimulated primary cilia on preosteoclasts promote periosteal-bone formation.

Article References:
Kim, JM., Lee, YS., Kim, M.J. et al. Exercise-stimulated primary cilia on preosteoclasts promote periosteal-bone formation. Exp Mol Med (2026). https://doi.org/10.1038/s12276-026-01765-5

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01765-5

Keywords: Primary cilia, preosteoclasts, mechanotransduction, periosteal bone formation, exercise, bone remodeling, skeletal mechanobiology, osteogenic signaling, polycystin complex, Hedgehog pathway, bone health, osteoporosis

One of the emerging therapeutic approaches targets sclerostin, a protein that inhibits bone formation by osteoblasts. Anti-sclerostin therapies have demonstrated promise by reactivating dormant bone lining cells (BLCs), a subset of quiescent osteoblasts residing on inactive bone surfaces. These BLCs are essential for recruiting active osteoblasts to repair and strengthen bone. Despite these therapeutic advances, the molecular switches that govern the transition of these dormant cells back to an active state have remained elusive, hindering the optimization of treatment protocols.

Pioneering this quest for understanding, a research team led by Professors Sunghoon Kwon and Sang Wan Kim utilized an integrative, spatially resolved transcriptomic technique to dissect osteoblast activity in unprecedented detail. The methodology involved osteoblast-specific lineage tracing coupled with spatially resolved laser-activated cell sorting (SLACS), allowing researchers to observe gene expression changes within osteoblasts while preserving their three-dimensional context within bone tissue. This approach overcame significant challenges in identifying BLCs, which lack unique histological or genetic markers, and in distinguishing reactivated BLCs from newly recruited osteoblasts following anti-sclerostin treatment.

The investigators categorized osteoblasts into three functional states: active, inactive (quiescent), and reactivated post-treatment. Transcriptomic profiling revealed that reactivated osteoblasts bore striking molecular resemblance to their active counterparts, whereas inactive osteoblasts displayed a distinct gene expression signature. Crucially, the study unveiled the transforming growth factor beta (TGF-β) signaling pathway as a key regulator enforcing osteoblast quiescence. TGF-β signaling was markedly suppressed in active and reactivated osteoblast populations, indicating that inhibition of this pathway might release the brakes on dormant osteoblasts, promoting their reactivation.

Supplementary experiments in bone organoid cultures corroborated these findings. When exposed to TGF-β, osteoblasts adopted a BLC-like phenotype characterized by flattened morphology, decreased vertical cellular thickness, and reduced proliferative capacity. Conversely, blocking TGF-β signaling encouraged a shift away from dormancy, underscoring its pivotal role in maintaining osteoblast inactivity. These observations were further confirmed in lineage tracing mouse models, where administration of TGF-β promoted osteoblast quiescence, while TGF-β blockade facilitated reactivation.

Most strikingly, the combination of TGF-β blockade with anti-sclerostin therapy amplified osteoblast lineage cell number and thickness beyond what was achievable with anti-sclerostin treatment alone. This synergy underscores the therapeutic potential of dual-targeted intervention in osteoporosis. To emulate conditions of bone loss and musculoskeletal disuse, the research team employed a hindlimb unloading mouse model. Here, combined inhibition of TGF-β and sclerostin significantly augmented trabecular bone volume fraction and thickness, while simultaneously reducing trabecular separation more effectively than monotherapies.

Dynamic bone formation metrics echoed these improvements, revealing elevated rates of osteoblastic bone deposition with combined treatment regimes. Beyond promoting bone formation, TGF-β inhibition also diminished markers indicative of osteoclastic bone resorption, hinting at a dual mechanism of action—both enhancing bone regeneration and mitigating bone degradation. This multi-faceted influence suggests that targeting TGF-β signaling could recalibrate skeletal homeostasis more comprehensively than currently available treatments.

Despite these promising outcomes, the complexity of TGF-β signaling raises concerns regarding potential side effects, as its biological functions extend far beyond the skeletal system. Future investigations will need to rigorously evaluate the safety profile and therapeutic window of this combination approach before clinical translation. Nevertheless, identifying TGF-β as a molecular gatekeeper of osteoblast quiescence and activation opens an exciting avenue for enhancing anabolic osteoporosis therapies.

Current anabolic treatments like romosozumab have demonstrated efficacy by inhibiting sclerostin, yet their long-term application poses safety challenges and side effects that limit broader usage. The integration of TGF-β inhibition may enable potent yet safer bone regeneration strategies by reducing treatment duration and possibly attenuating adverse outcomes. This research heralds a shift towards precision medicine in osteoporosis, leveraging a deeper molecular understanding to design combination therapies tailored for rapid and robust bone restoration.

The implications of reactivating quiescent osteoblast populations extend beyond osteoporosis to broader musculoskeletal health, potentially impacting recovery from fractures, bone defects, and degenerative diseases. By harnessing spatially resolved transcriptomics and lineage tracing, this study exemplifies how cutting-edge technologies can unravel complex cellular interactions within intricate tissue environments, fostering translational breakthroughs. The collaboration between bioengineering and medical disciplines at Seoul National University exemplifies multidisciplinary synergy driving innovation in skeletal biology.

In summary, this seminal work delineates TGF-β signaling as a fundamental inhibitory axis that maintains osteoblast dormancy, with its suppression serving as a catalyst for reactivating bone-forming cells. Combined with sclerostin inhibition, targeting TGF-β could significantly enhance therapeutic outcomes for osteoporosis patients, mitigating fracture risk and improving quality of life. As further clinical investigations progress, this molecular insight promises to reshape therapeutic paradigms and offers hope for millions affected by osteoporosis worldwide.

Subject of Research: Cells

Article Title: Spatially resolved osteoblast-traced transcriptomics uncovers TGF-β as a combination target with sclerostin in osteoporosis

News Publication Date: 2-Apr-2026

References: DOI: 10.1038/s41413-026-00521-9

Image Credits: German Tenorio from Openverse

Keywords: Osteoporosis, Osteoblast, Bone Remodeling, TGF-β Signaling, Anti-sclerostin Therapy, Bone Lining Cells, Lineage Tracing, Spatial Transcriptomics, Bone Formation, Bone Resorption, Musculoskeletal Health