Bone Research最新文献

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.

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.

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.

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.