Abstract
The peripheral nervous system is critically involved in bone metabolism, osteogenesis, and bone remodeling. Nerve fibers of sympathetic and sensory origin innervate synovial tissue and subchondral bone of diathrodial joints. They modulate vascularization and matrix differentiation during endochondral ossification in embryonic limb development, indicating a distinct role in skeletal growth and limb regeneration processes. In pathophysiological situations, the innervation pattern of sympathetic and sensory nerve fibers is altered in adult joint tissues and bone. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters. Osteoblasts, osteoclasts, mesenchymal stem cells, synovial fibroblasts, and different types of chondrocytes produce distinct subtypes of adrenoceptors, receptors for vasointestinal peptide, for substance P and calcitonin gene-related peptide. Many of these cells even synthesize neuropeptides such as substance P and calcitonin gene-related peptide and are positive for tyrosine-hydroxylase, the rate-limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters modulate osteo-chondrogenic differentiation of mesenchymal progenitor cells during endochondral ossification in limb development. In adults, sensory and sympathetic neurotransmitters are critical for bone regeneration after fracture and are involved in the pathology of inflammatory diseases as rheumatoid arthritis which manifests mainly in joints. Possibly, they might also play a role in pathogenesis of degenerative joint disorders, such as osteoarthritis. All together, accumulating data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper limb formation during embryonic skeletal growth. In adults, they modulate bone regeneration, bone remodeling, and articular cartilage homeostasis in addition to their classic neurological actions.
Highlights
Clinical observations demonstrated the importance of the peripheral nervous system for maintaining body homeostasis and mediating organogenesis and tissue repair
In bone metabolism and bone remodeling, calcitonin gene-related peptide (CGRP) and Vasoactive intestinal peptide (VIP) have anabolic effects, inducing osteoblast activity and inhibiting osteoclastogenesis, whereas substance P (SP) has catabolic effects depending on its concentration
Effects of the sympathetic nervous system on bone homeostasis are complex; it is discussed that blocking signaling through β-ARs can prevent bone loss, suggesting that high catecholamine concentrations shift the balance toward bone resorption by inhibiting osteoblast differentiation
Summary
Clinical observations demonstrated the importance of the peripheral nervous system for maintaining body homeostasis and mediating organogenesis and tissue repair. Nerve fibers of sympathetic and sensory origin frequently innervate trabecular bone, periosteum, and fracture callus [6,7] They are involved in controlling vascularization and matrix differentiation during endochondral ossification in embryonic limb development [8], indicating a distinct role in modulating skeletal growth and limb formation processes. CGRP presumably exerts its anabolic action on bone cells by stimulating canonical Wnt signaling through stabilization of β-catenin and by inhibiting osteoblast apoptosis, favoring local bone formation All together, these data imply that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for proper osteogenic differentiation and bone metabolism during embryonic skeletal growth and bone regeneration in adults (that is, after fracture) in addition to their classic neurological actions
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