The research team, working at the Korea Research Institute of Bioscience and Bioscience-affiliated laboratories, took an approach that sidesteps a long-standing obstacle in the field. Bone marrow from children with Legg-Calvé-Perthes disease is scarce and difficult to study, and even when mesenchymal stromal cells, the body’s principal skeletal progenitors, are isolated from osteonecrotic bone, they carry the imprint of a diseased, inflamed, poorly perfused tissue environment. Any abnormality observed in such cells could reflect that hostile microenvironment rather than an intrinsic flaw. To separate the two, the researchers reprogrammed skin fibroblasts from two patients with the disease, and from a healthy donor, into induced pluripotent stem cells using a non-integrating Sendai virus system that delivers the reprogramming factors OCT4, SOX2, KLF4 and c-MYC. Because skin cells can be reset to an embryonic-like state and then steered into mesenchymal stem cells under identical, standardized conditions, any difference that emerges between patient-derived and healthy cells must be written into the cells themselves rather than imposed by the tissue around them.

The quality control on this cellular reset was rigorous. The resulting induced pluripotent stem cell lines formed compact colonies with the characteristic morphology of embryonic stem cells, stained strongly for alkaline phosphatase, and expressed the canonical pluripotency markers OCT4, NANOG, TRA-1-60, TRA-1-81, SSEA-3 and SSEA-4 at levels comparable across all three lines. Quantitative PCR confirmed expression of OCT4 and REX1 in the undifferentiated state, and when the cells were allowed to spontaneously differentiate into embryoid bodies, they activated ectodermal markers such as SOX1 and PAX6, mesodermal markers including HAND1 and PDGFRA, and endodermal markers SOX7 and AFP. Immunostaining for TUJ1, NESTIN, DESMIN, alpha-SMA, FOXA2 and SOX17 confirmed protein-level differentiation into all three germ layers, and teratoma assays in immunodeficient mice produced tissues representing ectoderm, mesoderm and endoderm. G-band karyotyping showed normal diploid chromosomes in every line, ensuring that any phenotype found later was not an artefact of culture stress or genomic instability.

With validated stem cell lines in hand, the team differentiated them into induced mesenchymal stem cells using a defined, xeno-free protocol, first patterning the cells toward the mesodermal lineage for four days and then maturing them for a further seventeen days on fibronectin-coated plates. Flow cytometry confirmed that the resulting cells expressed the canonical mesenchymal markers CD73 and CD105 and lacked the haematopoietic markers CD34 and CD45, consistent with bona fide MSC identity. One subtlety stood out: the two patient-derived lines expressed CD90, a surface glycoprotein involved in adhesion and MSC immunophenotype, at only about sixty to seventy percent of the level seen in healthy donor cells, which reached roughly ninety-five percent. Proliferation rates, however, were indistinguishable between the groups, meaning the patient cells grew normally even as they showed this subtle phenotypic deviation, hinting that the real differences lay deeper, in what the cells could become rather than how fast they could multiply.

What the cells could become turned out to be the central finding. Under osteogenic induction, healthy donor cells produced abundant mineralized matrix, revealed by intense Alizarin Red S staining, and strongly upregulated the osteoblast genes RUNX2 and BGLAP. Both patient-derived lines formed dramatically fewer mineral deposits and mounted only weak induction of the same genes. Adipogenesis fared no better: healthy cells accumulated plentiful lipid droplets stained by Oil Red O and induced the adipogenic regulators PPARG and ADIPOQ, while patient cells showed markedly reduced lipid accumulation and gene induction. Chondrogenesis, assessed by Alcian Blue staining of sulfated glycosaminoglycans and by expression of SOX9 and COL2A1, was also reduced but comparatively better preserved. Crucially, this pattern of a simultaneous, broad suppression of all three mesenchymal lineages argues against the classic idea of a simple lineage shift, in which bone-forming cells are diverted into fat cells. Instead, it points to a deeper loss of overall differentiation competence within the patient-derived progenitors themselves.

The molecular culprit emerged when the researchers examined the Wnt/beta-catenin pathway, the master regulator of mesenchymal lineage commitment. Beta-catenin, the transcriptional co-activator at the heart of canonical Wnt signalling, promotes osteogenesis and chondrogenesis while restraining adipogenesis, and its intracellular abundance is normally kept in check by glycogen synthase kinase-3, which phosphorylates beta-catenin and tags it for proteasomal destruction. In the patient-derived cells, the team found a striking double abnormality. Transcripts for CTNNB1, the gene encoding beta-catenin, were significantly reduced, while GSK3B mRNA was markedly elevated. At the protein level, phosphorylation of GSK3alpha at Tyr279 and GSK3beta at Tyr216, the modifications associated with enhanced enzymatic activity, was substantially increased, reaching roughly 1.8- to 2.2-fold above healthy donor levels in the more severely affected patient line. Total beta-catenin protein and intracellular beta-catenin fluorescence were correspondingly diminished, painting a coherent picture of a kinase pushed into overdrive and a key transcriptional regulator destroyed faster than it should be.

The disease signature extended into inflammation, a domain long suspected to matter in this condition because children with active disease show elevated IL-6 and HMGB1 in synovial fluid. Even without any inflammatory stimulus, the patient-derived mesenchymal cells expressed higher baseline levels of IL6, PTGS2 and CCL2, indicating a primed inflammatory state. When the cells were challenged with IL-1beta, the patient cells responded with larger fold increases in these cytokines than healthy cells, and the Wnt target genes AXIN2 and LEF1, already slightly reduced at baseline, were driven down even further. Western blotting showed that IL-1beta pushed GSK3 phosphorylation higher in patient cells than in controls while beta-catenin, already low, declined still more. These exaggerated responses persisted after osteogenic differentiation, where patient-derived osteoblasts displayed stronger NF-kappaB phosphorylation and greater degradation of its inhibitor I-kappa-B-alpha upon inflammatory stimulation. Transcriptomic sequencing reinforced the theme, revealing enriched alterations in inflammatory signalling, extracellular matrix organization and Wnt-related regulatory pathways in both patient fibroblasts and patient-derived mesenchymal cells, with upregulation of multiple extracellular Wnt antagonists including DKK1, SFRP1, SFRP2, WIF1 and SOST.

The most striking result, and the one with the clearest translational implication, came next. When the researchers treated the patient-derived cells with lithium chloride, a long-established inhibitor of GSK3, beta-catenin fluorescence recovered to levels comparable to untreated healthy donor cells, with the rescue being strongest precisely where the deficit had been greatest. More importantly, the functional defect yielded to the same treatment. Lithium chloride substantially increased mineralized nodule formation and Oil Red O staining in both patient lines during osteogenic and adipogenic induction, and quantitative PCR confirmed that either lithium chloride or the more selective inhibitor CHIR99021 significantly boosted expression of BGLAP, RUNX2, ADIPOQ and PPARG. The differentiation programs had not been deleted; they had merely been silenced by an overactive kinase, and silencing the kinase switched them back on. This established that the mesenchymal failure in Legg-Calvé-Perthes disease reflects a reversible, kinase-dependent signalling imbalance rather than irreversible cellular damage.

The study’s authors are careful to place their findings in context. Observations in patients, such as elevated circulating leptin and increased adipose tissue within the affected femoral head, reflect systemic and tissue-level changes that arise from ischemia, inflammation and altered marrow mechanics, and the in vitro reduction in adipogenesis seen here does not contradict that clinical picture. Rather, the platform isolates the intrinsic cellular component of the disease, complementing animal models in which ischemia was surgically induced in piglets and rodents. Those models have shown that ischemia activates hypoxia-inducible factor 1-alpha and drives inflammatory and angiogenic responses, and the new human data now connect those tissue-level events to a specific, druggable intracellular node inside the progenitors that must rebuild the bone. The authors propose a reciprocal feedback loop in which inflammatory activation sustains GSK3 activity, further destabilizing beta-catenin and progressively compromising skeletal regeneration.

For a disease whose current treatments range from conservative containment to major reconstructive surgery, the prospect of a pharmacological strategy that restores the bone-building capacity of a child’s own progenitor cells is genuinely exciting. Lithium is an old drug with a well-characterized safety profile in other contexts, and the iPSC-based model developed here provides a patient-specific testing ground for optimizing GSK3-targeted regenerative therapies before they reach the clinic. Much work remains, including validating the findings in larger patient cohorts and determining how a GSK3 inhibitor could be delivered safely to the developing femoral head. But the central message stands: the cellular failure underlying a devastating childhood hip disease is not a life sentence written into the genome, but a reversible regulatory state, and with the right key, the machinery of skeletal repair can be switched back on.

Subject of Research: Reversible GSK3/beta-catenin dysregulation in patient-derived iPSC-mesenchymal stem cells from children with Legg-Calvé-Perthes disease

Article Title: Patient‐Derived iPSC‐MSC Modelling Reveals Reversible GSK3‐Mediated Suppression of Mesenchymal Lineage Differentiation in Legg‐Calvé‐Perthes Disease

Article References: Seol, B., Lim, H. J., Song, C. L., Lee, J., & Cho, Y. S. (2026). Patient‐Derived iPSC ‐ MSC Modelling Reveals Reversible GSK3 ‐Mediated Suppression of Mesenchymal Lineage Differentiation in Legg‐Calvé‐Perthes Disease. Journal of Cellular and Molecular Medicine, 30(17), Article e71350. https://doi.org/10.1111/jcmm.71350

Image Credits: AI Generated

DOI: 10.1111/jcmm.71350

Keywords: Legg-Calvé-Perthes disease, induced pluripotent stem cells, mesenchymal stem cells, GSK3, beta-catenin, Wnt signalling, osteonecrosis, osteogenesis, inflammation, lithium chloride, CHIR99021, paediatric orthopaedics

The experimental agent, known as E7386, belongs to a relatively new class of medicines called protein–protein interaction inhibitors. Rather than blocking an enzyme’s active site, it physically prevents the CREB-binding protein (CBP) from docking with β-catenin, a transcriptional co-activator that sits at the heart of the Wnt signalling pathway. When the CBP–β-catenin interaction proceeds unchecked, tumour cells receive a continuous stream of pro-growth and pro-survival instructions. Preclinical work had shown that E7386 suppressed intestinal polyp formation in genetically predisposed mice and shrank tumours in models where the Wnt pathway was overactive, and that combining the drug with lenvatinib — a multi-kinase inhibitor that starves tumours of their blood supply — produced greater antitumour activity than either drug alone in endometrial cancer models, regardless of whether tumours carried mutations in the CTNNB1 gene that encodes β-catenin.

The clinical context is stark. Endometrial cancer incidence is rising worldwide, and while the addition of immunotherapy to first-line chemotherapy has transformed outcomes for many patients, roughly 15 percent of women are diagnosed with advanced-stage disease, for whom five-year survival hovers around 15 to 17 percent. Once a patient’s tumour progresses after platinum-based chemotherapy and an anti-PD-(L)1 immune checkpoint inhibitor, second-line chemotherapy regimens deliver response rates of only about 15 percent. Antibody–drug conjugates have shown encouraging activity in this setting, but they require intravenous infusion and raise concerns about cross-resistance between agents sharing similar payloads, creating a genuine need for orally administered alternatives.

Study 102 enrolled 30 women between January 2023 and May 2024 across 12 sites in Japan, the Republic of Korea, and the United States. All had advanced, unresectable, or recurrent endometrial cancer that had progressed on or after platinum chemotherapy and an anti-PD-(L)1 agent such as pembrolizumab, durvalumab, or dostarlimab. Sixteen of the 30 had already been treated with lenvatinib itself. Participants received E7386 at 120 milligrams twice daily, with the lenvatinib starting dose later reduced from 20 to 14 milligrams once daily after non-clinical data suggested the combination retained its potency even at the lower dose — a change that also widened access for patients previously exposed to the drug.

The efficacy results exceeded what the heavily pretreated population would normally be expected to achieve. Eleven patients had confirmed responses — one complete and ten partial — for an objective response rate of 36.7 percent, roughly double the activity of conventional second-line chemotherapy. Responses proved durable, with a median duration of 9.1 months, and the disease control rate, which counts stable disease as well as shrinkage, reached 70 percent. Median progression-free survival was 5.5 months overall, and median overall survival had not been reached at the data cut-off, with 70 percent of patients alive at both six and twelve months.

The subgroup breakdown was particularly striking. Among the 14 women who had never received lenvatinib, the objective response rate climbed to 57.1 percent, with a median progression-free survival of 10.8 months — figures that compare favourably even with recent antibody–drug conjugate trials in the post-immunotherapy setting. Perhaps more surprising, three of the 16 patients who had already been treated with lenvatinib also responded, including two whose most recent prior therapy had been lenvatinib combined with pembrolizumab. This suggests that E7386 may re-sensitise tumours to lenvatinib’s mechanism, potentiating its antitumour activity rather than simply adding an independent effect.

Safety data supported the combination’s feasibility. Every patient experienced some treatment-emergent adverse event, but the most common — vomiting in 73.3 percent and nausea in 66.7 percent — were predominantly grade 1 or 2 and were largely controlled with standard anti-nausea medications such as 5-HT3 receptor antagonists. No grade 4 or 5 events occurred, and only two patients discontinued treatment because of toxicity. Dose interruptions and reductions were common, particularly for lenvatinib, reflecting the familiar fingerprint of that drug: proteinuria, diarrhoea, and hand–foot skin reactions appeared at rates consistent with its established profile. Because agents targeting the Wnt pathway have previously been linked to bone fragility, the investigators monitored bone density and bone turnover markers throughout; bone events occurred in just three patients, all manageable with supplements or antiresorptive therapy.

Biomarker analyses added a layer of molecular context. Circulating tumour DNA sequencing at baseline identified TP53 mutations as the most frequent alteration, present in 46.7 percent of patients, followed by mutations in KRAS, PIK3CA, PPP2R1A, PTEN, and FBXW7. Notably, a multivariate analysis adjusting for age, mismatch repair status, and prior lenvatinib exposure found no association between TP53 mutation status and any clinical outcome, and responses were seen across mismatch repair proficient and deficient tumours alike. With only 30 participants, however, the study was not powered to detect subtle predictive signatures, and the authors caution that the molecular findings are exploratory.

The trial’s limitations are real but typical of early-phase oncology research: a single-arm design without a control group, a small sample concentrated at Asian sites, and a population skewed toward patients with good performance status. Even so, the enrolled cohort closely mirrors the real-world post-immunotherapy population, with more than 80 percent having received at least two prior lines of systemic therapy. Against benchmarks such as the roughly 15 percent response rate of second-line chemotherapy, the 21 percent of lenvatinib monotherapy, and the 22 percent of sacituzumab govitecan in a mixed immunotherapy-exposed population, the 36.7 percent response rate — and 57.1 percent in lenvatinib-naïve patients — stands out.

The programme is already moving forward. A randomised dose-optimisation phase is now enrolling a more geographically balanced population of lenvatinib-naïve patients with advanced endometrial carcinoma, comparing two doses of E7386 plus lenvatinib against lenvatinib monotherapy or physician’s choice chemotherapy with doxorubicin or paclitaxel. If those results confirm the signals seen here, an all-oral regimen targeting the Wnt pathway and tumour vasculature could become a genuinely new option for women who currently have none — and a demonstration that drugging protein–protein interactions, long considered near-impossible, is becoming practical medicine.

Subject of Research: E7386 plus lenvatinib for advanced endometrial cancer after platinum chemotherapy and anti-PD-(L)1 immunotherapy

Article Title: E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort

Article References: Lee, J.-Y., Hasegawa, K., Kim, B.-G., Berman, B., Suzuki, S., Corr, B., Yunokawa, M., Orr, D., Yamamoto, N., Soliman, P. T., Miller, D. S., Potdar, A. A., Sahara, T., Kimura, T., Dutta, L., Wu, J., McKenzie, J., & Kyi, C. (2026). E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort. eClinicalMedicine, 100, Article 104206. https://doi.org/10.1016/j.eclinm.2026.104206

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104206

Keywords: endometrial cancer, E7386, lenvatinib, CBP–β-catenin inhibitor, Wnt signalling, immunotherapy resistance, phase 1b/2 trial, anti-PD-(L)1, targeted therapy, protein–protein interaction inhibitor, progression-free survival, gynecologic oncology

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