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.