Skeletal muscle aging involves the progressive decline in mass and function of muscle tissue, significantly impacting mobility and quality of life in older adults. Central to this process is the functional deterioration of SCs, the primary muscle stem cells responsible for regeneration. Aging impairs SC self-renewal, activation, proliferation, and differentiation through mechanisms including telomere attrition, mitochondrial dysfunction, epigenetic dysregulation, and aberrant signaling pathways such as Notch/Wnt and TGF-β. Additionally, the aged microenvironment—marked by chronic inflammation, oxidative stress, fibro-adipogenic infiltration, immune dysregulation, and vascular decline—further suppresses SC activity. Recent advances in multidisciplinary research, encompassing single-cell genomics, epigenetics, and bioengineering, have deepened our understanding of these mechanisms. Emerging interventions, such as nutritional strategies, exercise, pharmacological agents, cell therapy, and gene editing, offer promising avenues for restoring SC function and rejuvenating muscle regeneration. Future efforts should focus on integrated, personalized approaches to combat sarcopenia and improve healthspan.
Macrophage lipid metabolism is a pivotal regulator of bone homeostasis. Macrophages orchestrate the balance between bone resorption and formation primarily through their M1/M2 polarization states, with M1 macrophages promoting resorption and M2 macrophages supporting formation. This review comprehensively describes how key lipid metabolic pathways, such as fatty acid oxidation (FAO) and cholesterol metabolism, govern this polarization and subsequent bone remodeling. It integrates the core mechanisms by which lipid metabolism drives M1 and M2 polarization, and highlights that targeting macrophage lipid metabolism represents a promising therapeutic strategy for bone diseases. Finally, we identify emerging frontiers, including the “gut-bone axis” and epigenetic regulation, as critical directions for future research.
Many craniofacial disorders linked to mutations in enhancer-associated chromatin modifiers, including Kabuki syndrome (KS), present with skeletal abnormalities. KS is a craniofacial developmental disorder characterized by mutations in KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase. The cellular origins and molecular pathways leading to KMT2D-dependent skeletal deficits in KS are not well characterized. We previously demonstrated that KMT2D deletion in mouse cranial neural crest cells (cNCCs), multipotent stem cells contributing to craniofacial structures, impairs chondrocyte hypertrophic differentiation. Although we observed defects in cNCC endochondral ossification, KMT2D’s broader skeletal role remains unclear and its functional redundancy in skeletal development with its paralog, KMT2C, is understudied. We now find that KMT2D mutation within chondrocyte lineages results in postnatal growth defects. Chondrocytes deficient in both methyltransferases yield severe deficits in bone formation, revealing redundant roles for KMT2C/D in endochondral ossification. These methyltransferases regulate chondrocyte state transitions as hypertrophic differentiation is impaired with loss of KMT2C/D. When both methyltransferases are deleted in stem cell lineages, cNCCs fail to induce factors downstream of SOX9 activation. At the molecular level, H3K4me1 is lost at de novo chondrocyte enhancers essential for skeletal development, accompanied by reduced H3K27ac deposition, indicating KMT2C/D-dependent enhancer priming. We indicate roles for KMT2C/D in facilitating activation of genes downstream of SOX9 and RUNX2 transcription factors. Our findings define a regulatory cascade mediated by chromatin-level modifications to ensure commitment of chondrocyte lineages, expanding the known roles of histone modifiers and offering insights into the epigenetic underpinnings of skeletal dysplasia and related congenital disorders.
Collagen X, encoded by the Col10a1 gene, is expressed specifically by hypertrophic chondrocytes (HCs) in the cartilage. Mutations of the Col10a1 gene in humans, which increase the endoplasmic reticulum (ER) stress in HCs, lead to metaphyseal chondrodysplasia type Schmid (MCDS). However, the mechanism of how HCs respond to ER stress to affect bone development and growth is not entirely understood. In this study, we generated a new mouse model harboring a 13 bp deletion (13del) in the endogenous Col10a1 gene. These 13del-MCDS mice display all the known clinical characteristics of human MCDS, as well as the molecular and cellular changes within the growth plate cartilage. For the first time, we found that triggering ER stress leads to activation of hypoxia and HIFs pathways in vivo, promoting cellular survival in HCs of the 13del-MCDS mice. To test whether the activated hypoxia and HIFs pathways are triggered by ER stress or extrinsic factors, we generated WT/GFP-MCDS chimera mice. Our findings showed that the activation of hypoxia and the hypoxic pathway is an intrinsic response to ER stress, which may partly occur through activation of ATF4 in HCs of mice. In parallel, p53 pathway changes and autophagy-associated protein-quality-control responses were observed in spatial association with altered chondrocyte differentiation and survival. These findings reveal coordinated engagement of multiple stress-response pathways during the adaptive response of hypertrophic chondrocytes to chronic ER stress.
Osteoarthritis is a whole-joint disease in which cartilage loss, synovial inflammation, subchondral bone remodelling and pain-related neural changes co-evolve, yet structural improvement does not reliably translate into pain relief. This Review centres prostaglandin E2 (PGE2) skeletal interoception in the translational framework for 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibition. In skeletal interoception, PGE2 produced in mechanically stressed bone and osteochondral tissues is sensed by prostaglandin E receptor 4 (EP4)-positive sensory afferents, relayed to central circuits and translated into altered sympathetic norepinephrine output. Because 15-PGDH catabolises PGE2, its inhibition may prolong the persistence and spatial reach of this interoceptive cue while also acting locally on chondrocyte state. This combined local and interoceptive action offers a plausible mechanism for cartilage repair and pain modulation, but may also create compartment-specific risk when prolonged PGE2 persists in synovium or subchondral bone. We compare 15-PGDH inhibition with upstream synthesis blockade and receptor-specific strategies, and propose that development should be organised around three checkpoints: cartilage-enriched exposure, durability under mechanical load and structure–pain coherence. Current evidence supports cautious development rather than broad generalisation; clinical translation will require compartment-resolved pharmacokinetics/pharmacodynamics, EP-receptor attribution and early surveillance for synovial, osteochondral and pain-system liabilities.
