Jul 2026· Advancement of science· pp.
e76788
· 0 citations· 44 references
Medicine
TL;DR
It is shown that dysregulated endocrine function of skeletal muscle promotes bone loss through YAP1-driven pathogenic FAPs secreting IL-6 and FGF21, identifying FAP-derived IL-6 and FGF21 as key mediators of muscle-bone crosstalk and establishing the YAP-FAP-myokine axis as a therapeutic target for preventing bone loss in sarcopenia and osteoporosis.
Abstract
Sarcopenia, an age-related degenerative disease of skeletal muscle, is closely associated with osteoporosis and other bone disorders, partly due to dysregulated endocrine function of skeletal muscle. However, the specific cellular sources and molecular mechanisms driving this pathological secretory phenotype remain poorly defined. Using three distinct aging murine models, including sedentary controls, treadmill exercise-trained (TE) mice, and botulinum toxin A (BTXA)-induced muscle atrophy, combined with human cohort analysis, we investigated muscle-bone crosstalk. Fluorescence-activated cell sorting (FACS) was used to isolate fibro-adipogenic progenitors (FAPs). FAP-specific genetic manipulations, including conditional knockout (cKO) mice and adeno-associated virus-mediated knockdown, together with pharmacological inhibition of YAP1, were employed to dissect the mechanistic link between muscle secretory dysfunction and bone metabolism. We demonstrate that pathogenic activation of FAPs serves as a critical cellular source of bone-catabolic myokines during muscle atrophy. In a human cohort of older individuals with sarcopenia, osteoporosis, or osteosarcopenia, FAP numbers were significantly increased and correlated positively with sarcopenia traits and IL-6 and FGF21 levels. In mice, muscle wasting drives FAP accumulation through YAP1-mediated mechanotransduction, characterized by enhanced proliferation, suppressed apoptosis, and acquisition of a profibrotic phenotype concomitant with elevated IL-6 and FGF21 secretion. Using FAP-specific Il6 or Fgf21 knockdown, we showed that genetic ablation of these myokines in FAPs rescued trabecular bone loss despite persistent muscle atrophy. Mechanistically, YAP1 functions as a central regulator of this pathogenic secretory phenotype; FAP-specific Yap1 overexpression may contribute to the myokine dysfunction and bone loss, while FAP-specific Yap1 deletion or pharmacological inhibition diminished bone-loss-related myokine production and ameliorated bone deterioration. FAP-specific Yap1 cKO mice demonstrated that endogenous YAP1 is essential for pathogenic FAP activation and subsequent bone loss. Furthermore, therapeutic targeting of the FAP-YAP1-myokine axis provided robust skeletal protection in ovariectomy-induced postmenopausal osteoporosis. These findings reveal that dysregulated endocrine function of skeletal muscle promotes bone loss through YAP1-driven pathogenic FAPs secreting IL-6 and FGF21, identifying FAP-derived IL-6 and FGF21 as key mediators of muscle-bone crosstalk and establishing the YAP1-FAP-myokine axis as a therapeutic target for preventing bone loss in sarcopenia and osteoporosis.
Dysregulation of α-KG and L-2HG drives diabetic muscle fibrosis by disrupting TET2-dependent DNA hydroxymethylation and FAP division symmetry, supporting a TET2-dependent mechanism underlying the epigenetic effects of α-KG.
Zhou-Jie Tong, Yihui Li, Ming Song et al.· Metabolism: Clinical and Exp...· 1 citation
BACKGROUND
In idiopathic pulmonary fibrosis (IPF), inflammatory signaling and fibrotic remodeling often coexist, yet the mechanism linking these processes remains unclear. Numb, a cell fate determinant protein, has been implicated in tissue remodeling but its role in inflammation - fibrosis coupling is not well defined.
METHODS
Public transcriptomic datasets were analyzed to assess NUMB expression patterns and associated pathways. A bleomycin (BLM)-induced mouse model was used for in vivo validation. In vitro, MRC-5 fibroblasts were stimulated with IL-1β and TGF-β1, alone or in combination, followed by Numb siRNA intervention. Cell viability, migration, cytokine secretion, and fibrosis-related protein expression were evaluated.
RESULTS
Transcriptomic analysis showed a non-significant but consistent upward trend of NUMB in IPF tissues (p = .18), with pathway-level enrichment in inflammatory and extracellular matrix processes. In BLM-treated mice, IL-1β and TGF-β1 levels were significantly increased (both p < .001), accompanied by upregulation of Numb (p < .05), α-SMA, and Collagen I (both p < .001). In vitro, IL-1β and TGF-β1 synergistically enhanced cell viability and migration (both p < .001), as well as protein expression (p < .001). Numb silencing reduced cytokine secretion (p < .001), cell activation (p < .05-0.001), and fibrosis-related protein expression (p < .001).
CONCLUSION
Numb participates in coordinating inflammatory and fibrotic responses in IPF and may act as a regulatory mediator in inflammation - fibrosis coupling.
Debin Zhuo, Shanzuan Wang, Juan Lin et al.· Immunological Investigations· 0 citations
Introduction Atrophic non-union is a significant clinical challenge associated with impaired early inflammation resolution and delayed osteogenesis. Although the osteoimmune microenvironment is critical for bone healing, the specific molecular mechanisms regulating this process require further elucidation. Methods We utilized a 6-mm critical-size rat femoral defect model and time-series RNA sequencing to explore potential molecular mechanisms. Additionally, primary mouse bone marrow-derived macrophages (BMMs) were used for in vitro validation of in vivo findings. Results Histological and transcriptomic analyses identified 1-2 weeks post-fracture as a critical window characterized by significant inhibition of the canonical BMP9-SMAD signaling cascade in the non-union microenvironment. In vivo, this defect was associated with sustained accumulation of M1 macrophages, impaired reparative M2 polarization, and osteoclast-mediated bone resorption. In vitro studies further validated the in vivo results, confirming that BMP9 promotes M2 macrophage polarization, upregulates chemokines Ccl2 and Ccl7, and inhibits RANKL-induced osteoclastogenesis through the canonical SMAD-ID1 pathway. Discussion Early loss of canonical BMP9-SMAD signaling disrupts the balance between immune cell recruitment and bone remodeling, contributing to the development of atrophic non-union in critical-size defects. Targeted modulation of the BMP9-driven osteoimmune axis may offer a potential therapeutic strategy for impaired bone healing.
Kai Zhong, Yufei Shao, Yu Zhou et al.· Frontiers in Endocrinology· 0 citations
Aging induced chronic inflammation deteriorated bone loss in elderly population. This study aimed to investigate the underling mechanism of bone-immune crosstalk with aging. In clinical, we identified novel inflammatory markers as predictors for osteoporosis in old people, indicating a close relationship between immune system and bone strength. In animal study, more pro-inflammatory macrophages (M1) was identified in aged bone, suggesting a possible mechanism sheered by the altered bone-inmmune interplay. Transcriptomic analyses on senescent bone marrow mesenchymal stem cells (MSCs) suggested that immune signaling and osteoclasts differentiation were involved in MSCs aging. Moreover, single-cell sequencing data analyses (GSE145477) screened 4 co-deferentially expressed genes in this bone-immune system with aging. They were TREM2, TYROBP (encodes DAP12), SYK, and PIK3CD. Then, we established cells co-culture system and verified the age-reduced TREM2 accompanied with DAP12-SYK inactivation, leading to more M1 polarization. Conditioned medium experiments results were consistent with these changes. Pharmacological activation of TREM2-DAP12-SYK axis by a small molecule compound, ADAM10 inhibitor, recovered the macrophages aging and decreased their pro-inflammatory polarization. Therefore, we speculated that the increased M1 polarization by aging-reduced TREM2-DAP12-SYK signaling might be responsible for inflammatory micro-environment in bone tissue. Together, this study elaborated the bone-immune crosstalk with aging through the inflammatory signaling alteration and provided new treatment targets for senile osteoporosis.
Ziyi Liu, Yushan Li, Yu Zheng et al.· International Immunopharmaco...· 0 citations
It is demonstrated that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.
Lin Zhou, Yu Zhang, Xinxin Tan et al.· International Immunopharmaco...· 0 citations
Age-related sarcopenia is a progressive skeletal muscle disorder driven by oxidative stress and metabolic dysregulation. Cu/Zn superoxide dismutase-deficient (Sod1-/-) mice recapitulate key features of oxidative stress-induced muscle degeneration and provide a robust preclinical model for mechanistic and therapeutic studies. Here, we investigated whether systemic administration of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) could modulate muscle function and metabolic homeostasis under both pathological and physiological conditions. In Sod1-/- mice, UC-MSC treatment significantly improved motor coordination and grip endurance, restored gastrocnemius myofiber number, markedly reduced mitochondrial reactive oxygen species production and catalase expression levels in skeletal muscle, and restored muscle ATP content. UC-MSCs also restored circulating insulin-like growth factor-1 (IGF-1) levels. Untargeted lipidomic profiling revealed profound depletion of lipid species in Sod1-/- muscle, particularly omega-3 fatty acids, which was selectively rescued by UC-MSC therapy, including restoration of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, without substantial recovery of disrupted polar metabolic pathways such as aminoacyl-tRNA biosynthesis. In contrast, UC-MSC administration in wild-type mice induced a distinct metabolic remodeling characterized by reduced n-3 and n-6 fatty acid-associated lipid species and concomitant enrichment of fructose-related glycolytic intermediates, indicating a shift toward carbohydrate-based energy utilization in metabolically intact muscle. Together, these findings demonstrate that UC-MSCs function as context-dependent metabolic modulators, alleviating oxidative stress-induced sarcopenia through attenuation of oxidative stress, restoration of systemic IGF-1, and selective reprogramming of lipid metabolism, while dynamically adjusting energy metabolism in physiological skeletal muscle.
