Sympathetic regulation of bone homeostasis and remodeling: molecular mechanisms, pathophysiological roles, and...

Bone metabolic disorders, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, are characterized by disrupted skeletal homeostasis and represent major challenges in musculoskeletal health. Bone remodeling has long been interpreted as a coordinated process between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. However, emerging evidence indicates that bone is not merely a structural tissue, but a dynamic regulatory organ influenced by neural, endocrine, immune, metabolic, and vascular signals. Among these regulatory systems, the sympathetic nervous system (SNS) has attracted increasing attention as an important efferent pathway linking central physiological states with local skeletal remodeling. Sympathetic signals reach skeletal tissues through organized peripheral innervation and regulate bone-related cells through multiple pathways involving neurotransmitters, neuropeptides, receptors, and regulatory factors. Beyond direct regulation of osteoblasts, osteoclasts, osteocytes, chondrocytes, and skeletal progenitors, SNS-related pathways also shape the osteoimmune microenvironment by modulating immune-cell recruitment, macrophage polarization, cytokine production, inflammasome activation, and immune-related osteoclastogenesis. Dysregulation of these pathways contributes to bone-related disorders, including osteoporosis, osteoarthritis, rheumatoid arthritis-related bone destruction, intervertebral disc degeneration, and impaired fracture healing. By integrating anatomical, molecular, osteoimmune, and disease-related evidence, this review provides a comprehensive framework for understanding sympathetic regulation in bone metabolism and may support the development of more precise neuroregulatory strategies for skeletal diseases.