Bone resorption is a vital physiological process that enables skeletal remodeling, maintenance, and adaptation to mechanical forces throughout life. While tightly regulated under the physiological state, its dysregulation contributes to pathological conditions such as osteoporosis, rheumatoid arthritis, and periodontitis. Periodontitis is a highly prevalent chronic inflammatory disease driven by dysbiotic biofilms that disrupt the oral microbiome, leading to the progressive breakdown of the periodontal ligament, cementum, and alveolar bone and ultimately resulting in tooth loss. This review outlines the molecular and cellular mechanisms underlying periodontitis, focusing on osteoclastogenesis, the differentiation and activation of osteoclasts, the primary mediators of bone resorption. Key transcriptional regulators, including NFATc1, c-Fos, and c-Src are discussed alongside major signaling pathways such as Mitogen Activated Protein Kinase (MAPK), Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), Nuclear Factor Kappa B (NF-κB), and Phosphoinositide 3-kinase (PI3K)/Akt, to elucidate their roles in the initiation and progression of periodontal bone loss. These pathways orchestrate the inflammatory response and osteoclast activity, underscoring their relevance in periodontitis and other osteolytic conditions. Hallmark features of periodontitis, including chronic inflammation, immune dysregulation, and tissue destruction are highlighted, with emphasis on current and emerging therapeutic strategies targeting these molecular pathways. Special attention is given to small molecules, biologics, and natural compounds that have the potential to modulate key signaling pathways. Although advances in understanding these mechanisms have identified promising therapeutic targets, translation into effective clinical interventions remains challenging. Continued research into regulating bone-resorptive signaling pathways is essential for developing more effective treatments for periodontitis and related inflammatory bone diseases.

Bone is highly innervated, and its regeneration is significantly nerve-dependent. Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity. However, the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration. Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment, which is crucial for bone regeneration. This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment. We first discuss the changes in peripheral nerves during the regenerative process. We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment, emphasizing nerves, neural factors, and their impacts. Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration. A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous, immune, and skeletal systems to promote bone regeneration.

Traumatic spinal cord injury (SCI) is a debilitating condition characterized by the impairment of neural circuits, leading to the loss of motor and sensory functions and accompanied by severe complications. Substantial research has reported the therapeutic potential of Omega-3 fatty acids for the central nervous system, particularly after traumatic SCI. Omega-3 fatty acids may contribute to improving SCI recovery through their anti-inflammatory, anti-oxidative, neurotrophic, and membrane integrity-preserving properties. These functions of Omega-3 fatty acids are primarily mediated via the activation of G protein-coupled receptor 120 (GPR120), commonly known as the fish oil-specific receptor. Advancements in understanding of the molecular mechanisms of GPR120’s recognition of Omega-3 fatty acids and its downstream signaling mechanisms has significantly promoted research on the pharmacological potential of Omega-3 fatty acids and the development of highly selective and high-affinity alternatives. This review aims to provide in-depth analysis of the comprehensive therapeutic potential of Omega-3 fatty acids for SCI and its accompanying complications, and the prospects for developing novel drugs based on the recognition of Omega-3 fatty acids by GPR120.

The continuous extension of human life expectancy and the global trend of population aging have contributed to a marked increase in the incidence of musculoskeletal diseases, with fractures and osteoporosis being prominent examples. Consequently, promoting bone regeneration is a crucial medical challenge that demands immediate attention. As early as the mid-20th century, researchers revealed that electrical stimulation could effectively promote the healing and regeneration of bone tissue. This is achieved by mimicking the endogenous electric field within bone tissue, which influences cellular behavior and molecular mechanisms. In recent years, electroactive hydrogels responsive to electric field stimulation have been developed and applied to regulate cell functions at different stages of bone regeneration. This paper elaborates on the regulatory effects of electrical stimulation on MSCs, macrophages, and vascular endothelial cells during the process of bone regeneration. It also involves the activation of relevant ion channels and signaling pathways. Subsequently, it comprehensively reviews various electric-field-responsive hydrogels developed in recent years, covering aspects such as material selection, preparation methods, characteristics, and their applications in bone regeneration. Ultimately, it provides an objective summary of the existing deficiencies in hydrogel materials and research, and looks ahead to future development directions.

Bone fractures represent a significant global healthcare burden. Although fractures typically heal on their own, some fail to regenerate properly, leading to nonunion, a condition that causes prolonged disability, morbidity, and mortality. The challenge of treating nonunion fractures is further complicated in patients with underlying bone disorders where systemic and local factors impair bone healing. Traditional treatment approaches, including autografts, allografts, xenografts, and synthetic biomaterials, face limitations such as donor site pain, immune rejection, and insufficient mechanical strength, underscoring the need for alternative strategies. Biologic therapies have emerged as promising tools to enhance bone regeneration by leveraging the body’s natural healing processes. This review explores the critical role of conventional and emerging biologics in fracture healing. We categorize biologic therapies into protein-based treatments, gene and transcript therapies, small molecules, peptides, and cell-based therapies, highlighting their mechanisms of action, advantages, and clinical relevance. Finally, we examine the potential applications of biologics in treating fractures associated with bone disorders such as osteoporosis, osteogenesis imperfecta, rickets, osteomalacia, Paget’s disease, and bone tumors. By integrating biologic therapies with existing biomaterial-based strategies, these innovative approaches have the potential to transform clinical management and improve outcomes for patients with difficult-to-heal fractures.

The transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways are pivotal regulators of cellular processes, playing indispensable roles in embryogenesis, postnatal development, and tissue homeostasis. These pathways are particularly critical within the skeletal system, as they coordinate osteogenesis, chondrogenesis, and bone remodeling through intricate molecular mechanisms. TGF-β/BMP signaling is primarily transduced via canonical Smad-dependent pathways (e.g., ligands, receptors, and intracellular Smads) and the non-canonical Smad-independent (e.g., p38 mitogen-activated protein kinase, MAPK) cascade. Both pathways converge on master transcriptional regulators, including Runx2 and Osterix, and their precise coordination is indispensable for skeletal development, maintenance, and repair. The dysregulation of TGF-β/BMP signaling contributes to a spectrum of skeletal dysplasia and bone pathologies. Advances in molecular genetics, particularly gene-targeting strategies and transgenic mouse models, have deepened our understanding of the spatiotemporal control of TGF-β/BMP signaling in bone and cartilage development. Moreover, emerging research underscores extensive crosstalk between TGF-β/BMP and other critical pathways, such as Wnt/β-catenin, mitogen-activated protein kinase (MAPK), parathyroid hormone (PTH)/PTH-related protein (PTHrP), fibroblast growth factors (FGF), Hedgehog, Notch, insulin-like growth factors (IGF)/insulin-like growth factors receptor (IGFR), Mammalian target of rapamycin (mTOR), and autophagy, forming an integrated regulatory network that ensures skeletal integrity. Our review synthesizes the current knowledge on the molecular components, regulatory mechanisms, and functional integration of TGF-β/BMP signaling in skeletal biology, with an emphasis on its roles in development, regeneration, and disease. By elucidating the molecular underpinnings of TGF-β/BMP pathways and their contextual interactions, we aim to highlight translational opportunities and novel therapeutic strategies for treating skeletal disorders.

After injury, bone tissue initiates a reparative response to restore its structure and function. The failure to initiate or delay this response could result in fracture nonunion. The molecular mechanisms underlying the occurrence of fracture nonunion are not yet established. We propose that hypoxia-triggered signaling pathways, mediated by reactive oxygen species (ROS) homeostasis, control Bmp2 expression and fracture healing initiation. The excessive ROS leads to oxidative stress and, ultimately, fracture nonunion. In this study, we silenced Apex1, the final ROS signaling transducer that mediates the activation of key transcription factors by their cysteines oxidoreduction, evaluating its role during endochondral ossification and fracture repair. Silencing Apex1 in limb bud mesenchyme results in transient metaphyseal dysplasia derived from impaired chondrocyte differentiation. During bone regeneration, Apex1 silencing induces a fracture nonunion phenotype, characterized by delayed fracture repair initiation, impaired periosteal response, and reduced chondrocyte and osteoblast differentiation. This compromised chondrocyte differentiation hampers callus vascularization and healing progression. Our findings highlight a critical mechanism where hypoxia-driven ROS signaling in mesenchymal progenitors through APEX1 is essential for fracture healing initiation.

The lymphatic system is widely distributed in skeletal muscles, joints, and skeletal tissues and plays a key role in maintaining immune homeostasis, regulating inflammatory responses, and tissue repair. In recent years, an increasing number of studies have shown that morphological and functional changes in lymphatic vessels are closely associated with the onset and progression of a variety of musculoskeletal disorders (MSDs), such as osteoarthritis (OA), fractures, and muscular dystrophy. However, the specific mechanisms of the lymphatic system’s role in these diseases have not been fully elucidated, and their potential clinical value remains to be thoroughly explored. In this review, we review the recent research progress on the structure, function, and pathophysiological role of the lymphatic system in the musculoskeletal system, and we focus on the association between lymphangiogenesis, dysfunction, and MSDs, and systematically summarize the therapeutic strategies targeting the lymphatic system. In addition, we summarize the limitations of current studies and propose key directions for future research, with a view to providing new ideas for basic research and clinical intervention in MSDs.

Nociceptive pain is a cardinal feature of traumatic and inflammatory bone diseases. However, whether and how nociceptors actively regulate the immune response during bone regeneration remains unclear. Here, we found that neutrophil-triggered nociceptive ingrowth functioned as negative feedback regulation to inflammation during bone healing. A unique Il4ra⁺Ccl2^high neutrophil subset drove intense postinjury TRPV1⁺ nociceptive ingrowth, which in return dissipated inflammation by activating the production of pro-resolving mediator lipoxin A4 (LXA4) in osteoblasts. Mechanistically, osteoblastic autophagy activated by nociceptor-derived calcitonin gene-related peptide (CGRP) suppressed the nuclear translocation of arachidonate 5-lipoxygenase (5-LOX) to favor the LXA4 biosynthesis. Moreover, in alveolar bone from patients with Type II diabetes, we found diminished nociceptive innervation correlated with reduced autophagy, increased inflammation, and impaired bone formation. Activating nociceptive nerves by spicy diet or topical administration of a clinical-approved TRPV1 agonist showed therapeutic benefits on alveolar bone healing in diabetic mice. These results reveal a critical neuroimmune interaction underlying the inflammation-regeneration balance during bone repairing and may lead to novel therapeutic strategies for inflammatory bone diseases.

Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.

Bone sialoprotein (BSP) is a major non-collagenous protein of the bone extracellular matrix and an important regulator of bone formation and resorption. BSP is produced by bone cells and chondrocytes and present in the bone matrix, cells, dentin and cartilage. However, its aberrant expression in primary tumour tissues and the sera of cancer patients with metastases implicates BSP in tumour biology and progression. The Arg-Gly-Asp (RGD) motif of BSP may be crucial not only for the attachment of metastasising cells to the bone surface but also for tumour growth, survival and activity. This review examines the structure and functions of BSP, including its roles in angiogenesis, bone formation, osteoclast differentiation and activity and cancer cell proliferation, survival, complement evasion, adhesion, migration and invasion. Growing evidence highlights BSP as a key mediator of tumour pathophysiology, skeletal metastasis development and associated bone remodelling. These processes are driven through RGD-integrin binding, the integrin/BSP/matrix metalloproteinase axis, integrin-independent signalling pathways, epithelial-to-mesenchymal transition and potentially post-translational modifications. A deeper understanding of BSP’s role in tumour progression may reinforce its potential as a prognostic and diagnostic tumour biomarker and aid the development of anti-BSP antibodies or targeted inhibitors for skeletal metastases and bone diseases.

During aging, the spine undergoes degenerative changes, particularly with vertebral endplate bone expansion and sclerosis, that are associated with nonspecific low back pain. We report that parathyroid hormone (PTH) treatment reduced vertebral endplate sclerosis and improved pain behaviors in three mouse models of spinal degeneration (aged, SM/J, and young lumbar spine instability mice). Aberrant innervation in the vertebral body and endplate during spinal degeneration was decreased with PTH treatment as quantified by PGP9.5⁺ and CGRP⁺ nerve fibers, as well as CGRP expression in dorsal root ganglia. The neuronal repulsion factor Slit3 significantly increased in response to PTH treatment mediated by transcriptional factor FoxA2. PTH type 1 receptor and Slit3 deletion in osteocalcin-expressing cells prevented PTH-reduction of endplate porosity and improvement in behavior tests. Altogether, PTH stimulated osteoblast production of Slit3, decreased aberrant sensory nerve innervation, and provided symptomatic relief of LBP associated with mouse spinal degeneration.

Advanced age impairs bone fracture healing; the underlying mechanism of this phenomenon remains unknown. We determined that apolipoprotein E (ApoE) increases with age and causes poor fracture healing. After deletion of hepatic ApoE expression (ΔApoE), 24-month-old ΔApoE mice displayed a 95% reduction in circulating ApoE levels and significantly improved fracture healing. ApoE treatment of aged BMSCs inhibited osteoblast differentiation in tissue culture models; RNA-seq, Western blot, immunofluorescence, and RT-PCR analyses indicated that the Wnt/β-catenin pathway is the target of this inhibition. Indeed, we showed that ApoE had no effect on cultures with stabilized β-catenin levels. Next, we determined that Lrp4 serves as the osteoblast cell surface receptor to ApoE, as expression of Lrp4 is required in ApoE-based inhibition of Wnt/β-catenin signaling and osteoblast differentiation. Importantly, we validated this ApoE-Lrp4-Wnt/β-catenin molecular mechanism in human osteoblast differentiation. Finally, we identified an ApoE-neutralizing antibody (NAb) and used it to treat aged, wildtype mice 3 days after fracture surgery resulting in fracture calluses with 35% more bone deposition. Our work here identifies novel liver-to-bone cross-talk and a noninvasive, translatable therapeutic intervention for aged bone regeneration.

Osteoarthritis (OA) is a degenerative skeletal condition marked by the loss of articular cartilage and changes to subchondral bone homeostasis. Treatments for OA beyond full joint replacement are lacking primarily due to gaps in molecular knowledge of the biological drivers of disease. Mass Spectrometry Imaging (MSI) enables molecular spatial mapping of the proteomic landscape of tissues. Histologic sections of human tibial plateaus from knees of human OA patients and cadaveric controls were treated with collagenase III to target extracellular matrix (ECM) proteins prior to MS Imaging of bone and cartilage proteins. Spatial MS imaging of the knee identified distinct areas of joint damage to the subchondral bone underneath areas of lost cartilage. This damaged bone signature extended underneath remaining cartilage in OA joints, indicating subchondral bone remodeling could occur before full thickness cartilage loss in OA. Specific ECM peptide markers from OA-affected medial tibial plateaus were compared to their healthier lateral halves from the same patient, as well as to healthy, age-matched cadaveric knees. Overall, 31 peptide candidates from ECM proteins, including Collagen alpha-1(I), Collagen alpha-1(III), and surprisingly, Collagen alpha-1(VI) and Collagen alpha-3(VI), exhibited significantly elevated abundance in diseased tissues. Additionally, highly specific hydroxyproline-containing collagen peptides, mainly from collagen type I, dominated OA subchondral bone directly under regions of lost cartilage but not areas where cartilage remained intact. A separate analysis of synovial fluid from a second cohort of OA patients found similar regulation of collagens and ECM proteins via LC-MS/MS demonstrating that markers of subchondral bone remodeling discovered by MALDI-MS may be detectable as biomarkers in biofluid samples. The identification of specific protein markers for subchondral bone remodeling in OA advances our molecular understanding of disease progression in OA and provides potential new biomarkers for OA detection and disease grading.

Cells actively sense and transduce microenvironmental mechanical inputs into chemical signals via cytoskeletal rearrangements. During these mechanosensation and mechanotransduction processes, the role of the actin cytoskeleton is well-understood, whereas the role of the tubulin cytoskeleton remains largely elusive. Here, we report the dynamic changes in microtubules in response to microenvironmental stiffness during chondrocyte mitosis. Mechanical stiffness was found to be coupled with microtubule generation, directing microtubule dynamics in mitotic chondrocytes. Refilin B was found to be a key regulator of microtubule assembly in chondrocytes in response to mechanical stiffness. It was found to play its role in microtubule formation via the p-Smad3 signaling pathway. Additionally, integrin-linked kinase (ILK), triggered by mechanical stiffness, was found to play an indispensable role in the process of microtubule dynamics mediated by refilin B. Our data emphasizes stiffness-mediated dynamic changes in the microtubules of chondrocytes in a quiescent state (G0) and at anaphase, which improves our understanding of the mechanical regulation of microtubule assembly during the chondrocyte cell cycle and provides insights into microenvironment mechanics during tissue maintenance, wound healing, and disease occurrence.

Craniofacial development relies on the migration of cranial neural crest cells (CNCCs) to the first and second pharyngeal arches, followed by their differentiation into various cell types during embryogenesis. Although the CNCC migration has been well-studied, the role of the niche in relation to CNCC remains unclear. Variants in FOXI3 have been implicated in craniofacial microsomia (CFM), yet the molecular mechanisms remain unexplored. FOXI3 is expressed in the ectoderm and auricle epidermis, but not in CNCCs or cartilage. Deletion of Foxi3 in the mouse CNCCs did not disrupt mandible and auricular development, further confirming that FOXI3 does not directly regulate CNCCs. However, Foxi3 deficiency in the ectoderm reduced the production of chondrogenesis-related cytokines derived from ectodermal cells, such as TGF-β1. This impairment affected CNCC proliferation through cell communication, subsequently altering the development of the mandible and auricle. These results emphasize the critical role of FOXI3 in establishing the microenvironment supporting CNCC function. Furthermore, FOXI3 directly regulates target genes associated with translation, thereby orchestrating cytokine production in epidermal cells. The validation using auricle sample from a CFM patient carrying FOXI3 mutation further supports our findings. These insights highlight the function of FOXI3 in creating the niche necessary for CNCC development and provide a basis for understanding the molecular mechanisms driving CFM pathogenesis.

Irreversible fibrotic scarring after rotator cuff tear (RCT) compromises the mechanical properties of the healing tendon, yet the underlying mechanisms remain poorly understood. Here, we analyzed the histological features of human RCT scars, characterized by disruption of tendon architecture, disorganized collagen fibrils, and imbalance in type I/III collagen ratios and fibril diameters. Using single-cell RNA sequencing of tendon stumps from patients with RCT, we deconvolved the cellular and molecular landscape of the fibrotic scarring microenvironment. Heterogenous pro-fibrotic subclusters were identified and validated to participate into scar formation, including tendon stem cell, senescent tenocyte, SOX9-driven pro-fibrotic macrophage, and pro-fibrotic endothelial cells undergoing endothelial-mesenchymal transition (EndoMT). Furthermore, we found that osteopontin and TGF-β signaling were key drivers of extracellular matrix deposition, and their blockade ameliorated fibrotic scarring after RCT. Collectively, our study dissected the dynamic scarring microenvironment in human RCT and highlights potential therapeutic targets for preventing pathological scar formation.

Respiratory inflammatory diseases disrupt bone metabolism and cause pathological bone loss. The lung-bone axis is established in chronic diseases like asthma and cystic fibrosis but is less studied in acute lung injury (ALI), recently implicated in COVID-19-induced bone loss. This study examined the effects of LPS-induced ALI on bone phenotype and explored the role of 2-N, 6-O sulfated chitosan (26SCS) in mitigating pneumonia-induced bone loss via inflammatory response modulation. Our findings show that 26SCS effectively reaches bone tissue after oral administration. It promotes macrophage polarization to the M2 phenotype, alleviating immune cascade reactions and inhibiting osteoclast-mediated bone resorption. Increased M2 macrophages support type H vessel formation, enhancing inflammatory bone vascularization. These effects foster a favorable osteogenic microenvironment and mitigate ALI-induced bone loss. While dexamethasone is effective in reducing inflammation, it can aggravate ALI-induced bone loss. Our research offers a therapeutic strategy targeting the lung-bone axis for inflammation-induced bone loss.

Endochondral ossification is a physiological process involving a sequential formation of cartilage and bone tissues. Classically, cartilage and bone formation have been considered independent processes at cellular level. However, the recently described multiple cell differentiation dynamics suggest that some bone cells are indeed the progeny of cartilage cells, or chondrocyte-derived osteoblasts. We hypothesized that the cartilage-to-bone phenotype transition is triggered by specific molecular events. First, the process was assessed in mouse bone tissue, and then, it was mimicked using in vivo cell implantation and in vitro serial differentiation protocols. Data indicates that cartilage cells transition to bone cell phenotype during postnatal physiological bone formation. This process can be reproduced using cartilage precursor cells coupled to specific implantation procedures or differentiation protocols. Gene expression profiling reveals that NOTCH, BMP and MAPK signaling pathways are relevant at the phenotype-switch, while the transcription factors Mesp1, Alx1, Grhl3 and Hmx3 are the feasible driver genes for chondrocyte-derived osteoblasts formation. Altogether, this report shows that endochondral ossification can be modeled using primary cell cultures and data indicate that this process is regulated by specific molecular events, previously described at skeleton morphogenesis during embryo development, and from now on also linkable to postnatal bone development and regeneration processes.

Mitochondrial regulation in mesenchymal stem cells (MSCs) serves as a critical determinant of bone formation and skeletal homeostasis. While dietary nitrate and its transporter Sialin are implicated in systemic homeostasis, their specific roles in MSCs' function remain unclear. Here, we demonstrate that Sialin deficiency impairs MSCs' function and disrupts bone homeostasis. Gain- and loss-of-function studies reveal that Sialin localizes to the mitochondrial membrane and promotes osteogenic differentiation by maintaining mitochondrial bioenergetic integrity. Mechanistically, Sialin recruits pSTAT3^S727 to mitochondria, forming a functional complex that activates mitochondrial bioenergy and stabilizes bone remodeling. Notably, dietary nitrate restores Sialin expression in aged mice, thereby enhancing MSCs' function and preventing osteoporosis. Our findings identify a nutrient-responsive signaling axis—nitrate-Sialin-pSTAT3^S727—that promotes osteogenic differentiation via mitochondrial homeostasis, offering a potential therapeutic strategy for age-related osteoporosis.

Obesity and type-2 diabetes, two interconnected and increasingly prevalent metabolic disorders, are associated with poor bone quality, higher fracture risk, and impaired fracture repair. The causes are not yet resolved but appear to relate to the impaired glucose homeostasis, altered bone material properties and remodeling, and compromised skeletal vascularization. Each of these features is impacted by hypoxia-inducible factor (HIF) signaling, which led us to hypothesize that HIF pathway modulation might be an effective strategy to concomitantly improve energy metabolism and bone health in conditions of metabolic stress. Here, we evaluated whether pharmacological HIF activation using the HIF-prolyl-hydroxylase-domain enzyme (PHD) inhibitor FG-4592 (Roxadustat) could protect mice against the adverse skeletal and metabolic consequences of high-fat diet (HFD)-induced obesity. We found that systemic FG-4592 treatment effectively prevented HFD-triggered body weight gain, glucose intolerance, and peripheral fat accumulation, associated with globally increased energy expenditure. Concomitantly, FG-4592 administration prevented the skeletal vascular damage, marrow fat accumulation, and bone formation deficits that were caused by HFD. Moreover, the HIF-activating drug also improved glucose metabolism and bone regeneration in a model of compromised fracture repair associated with overnutrition. Specifically, short-term FG-4592 treatment during fracture recovery reduced the body weight and fat mass of obese mice, improved glucose tolerance, and enhanced the fracture bridging capacity, along with promoting callus vascularization. These findings demonstrate that systemic hypoxia signaling stimulation using PHD inhibitors alleviates both the metabolic and skeletal consequences of diet-induced obesity in mice, highlighting its potential as a dual-action therapeutic strategy for enhancing glucose homeostasis and bone health/regeneration in disorders of obesity and metabolic dysfunction.

Estrogen deficiency after menopause accelerates bone loss by stimulating osteoclast formation and activity, but the molecular pathways that link estrogen signaling to osteoclast regulation remain incompletely defined. Here, we identify the sialyltransferase ST3GAL-I as a key mediator of RANKL-induced osteoclastogenesis. RANKL activates c-FOS to drive ST3GAL1 transcription, whereas estrogen-bound ERα competes with TRAF6 and suppresses this c-FOS–dependent induction. In a clinical cohort of pre-menopausal and post-menopausal women with or without osteoporosis, serum total and α-2,3-linked sialic acid levels increased with age and were highest in post-menopausal osteoporotic patients. Single-cell RNA sequencing of human bone revealed that osteoclasts form a prominent cluster only after menopause, where FOS, CTSK, and ST3GAL1 are strongly co-expressed, and the estrogen-responsive gene PGR is down-regulated. Additionally, in vivo experiments showed that sialidase treatment in estrogen-deficient models effectively reduced osteoclast-mediated bone loss, mimicking the effects of estradiol. These findings define a direct molecular link between loss of estrogen and activation of a FOS–ST3GAL1 sialylation pathway in osteoclasts, providing mechanistic insight into the enhanced bone resorption characteristic of post-menopausal osteoporosis.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating condition resulting from the use of glucocorticoids, commonly prescribed for immune-related and inflammatory diseases. Understanding the mechanisms driving SONFH remains a significant challenge, complicating efforts to prevent and treat the condition. While genetic predispositions, impaired blood supply, and metabolic changes are recognized contributors, the complex interplay between these factors is not yet fully understood. Recent research has shed light on the pathogenesis of SONFH, exploring it from multiple perspectives, including tissue-level damage, cellular dysfunction, and molecular pathways. This review summarizes these recent advancements, providing an integrated understanding of the onset and progression of the condition. Additionally, it highlights emerging therapeutic strategies that potentially pave the way for more effective treatments in the future.

Skeletal aging associated with diverse age-related disorders is increasing due to unhealthy diets, stressful lifestyles, and rapid aging. Repair and regeneration of aging skeletons are a global issue. Despite the self-healing ability of bone and the availability of various treatment strategies, degenerative bone repair and regeneration face significant problems due to unbalanced bone remodeling and a lack of active treatment strategies. The development of smart materials has created opportunities for degenerative bone repair and regeneration. The smart materials are responsive to endogenous/exogenous stimuli with tailored structure and function, which can promote skeletal aging repair and regeneration. Thus, in this study, skeletal aging is recognized as the progressive state that begins from peak bone mass to pathophysiological state and disorder conditions. We have introduced and characterized skeletal aging from the perspectives of cell-matrix-microenvironment and macrostructure-function-mechanical properties, for which systemic smart drug delivery systems and local smart scaffolds are designed. The smart drug delivery systems undergo conformation change and phase transition upon stimuli to release drugs at time- and site-specific to promote aging bone repair. Smart scaffolds with versatility and mechanical strength can replace bone defects to provide a tissue repair and regeneration microenvironment. Endogenous disease microenvironments and/or external physical triggers stimulate scaffold activation, which release bioactive factors to accelerate bone regeneration. This manuscript discusses the manufacturing techniques of these smart materials and presents key challenges and future directions for clinical translation, emphasizing their potential for personalized treatment and targeted therapy of skeletal aging.

Bone regeneration is initiated after a bone injury, such as a bone fracture or tooth extraction. It is a highly complex biological process involving multiple cell types, signaling molecules, and molecular pathways. The hypoxic microenvironment in the early stage of bone regeneration poses challenges to cell status and the final outcome of bone regeneration. During this phase, two key regulators—HIF-1α (the critical mediator of hypoxia response) and BMAL1 (the central component of the circadian rhythm)—orchestrate the activities of bone-regenerating cells, ensuring proper cellular function and orderly progression of bone repair. Existing studies have shown that there is a close crosstalk between HIF-1α and BMAL1, including regulation of gene expression, protein interaction, and regulation of downstream pathways. In this review, we discuss the respective regulatory roles of HIF-1α and BMAL1 in bone regeneration and further summarize their interactions within cells. Additionally, we extend the discussion to their interactions in other bone-related diseases, and summarize the existing research directions and deficiencies, providing new insights for in-depth studies of the hypoxia response and circadian rhythm systems.

Osteoarthritis (OA) is an aging-related degenerative joint disease without effective therapies. In the early stage of OA, mild synovitis has been reported to induce cartilage lesions. A better understanding of crosstalk between synovial macrophages and chondrocytes are being developed to discover new OA therapeutics. Here, we identified that the extracellular vesicles (EVs) derived from synovial pro-inflammatory macrophages regulated the autophagy function of chondrocytes, induced the onset of cartilage degeneration in normal joints. Mechanistically, the active transfer of miR-155-5p via EVs from synovial pro-inflammatory macrophages to chondrocytes accelerates cartilage degeneration by suppressing GSK-3β/mTORC1 axis-mediated autophagy function during OA progression. Deleting miR-155 from synovial pro-inflammatory macrophages relieved cartilage lesions and synovitis in OA mice. On the other hand, Fragile X mental retardation protein (FMRP) selectively sorted miR-155-5p into EVs derived from synovial pro-inflammatory macrophages, and the levels of plasma EVs FMRP were closely related to OA progression, suggesting the potential candidate for diagnostic OA biomarkers. Based on these findings, we developed engineering EVs with MAP (pro-inflammatory macrophages-affinity peptide) derived from adipose-derived stromal cells (ADSCs) as the antagomiR-155-5p delivery vehicles which exhibited superior therapeutic effects on synovitis and injured cartilage in the surgery-induced OA rats. Furthermore, MAP-ADSCs-EVs were proved to target the polarization of synovial pro-inflammatory macrophages in the clinical OA samples. Collectively, our study indicates that plasma EVs FMRP and engineered MAP-ADSCs-EVs targeting synovial pro-inflammatory macrophages represent potential novel therapeutic strategy for the progression of OA.