Abstract
ABSTRACTThe innervation of bone has been described for centuries, and our understanding of its function has rapidly evolved over the past several decades to encompass roles of subtype‐specific neurons in skeletal homeostasis. Current research has been largely focused on the distribution and function of specific neuronal populations within bone, as well as their cellular and molecular relationships with target cells in the bone microenvironment. This review provides a historical perspective of the field of skeletal neurobiology that highlights the diverse yet interconnected nature of nerves and skeletal health, particularly in the context of bone anabolism and pain. We explore what is known regarding the neuronal subtypes found in the skeleton, their distribution within bone compartments, and their central projection pathways. This neuroskeletal map then serves as a foundation for a comprehensive discussion of the neural control of skeletal development, homeostasis, repair, and bone pain. Active synthesis of this research recently led to the first biotherapeutic success story in the field. Specifically, the ongoing clinical trials of anti‐nerve growth factor therapeutics have been optimized to titrated doses that effectively alleviate pain while maintaining bone and joint health. Continued collaborations between neuroscientists and bone biologists are needed to build on this progress, leading to a more complete understanding of neural regulation of the skeleton and development of novel therapeutics. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
Highlights
The field of skeletal neurobiology emerged with a great debate surrounding the relationship between sensory nerve damage and joint disease that began in the mid‐19th century
In the 1980s, a third theory emerged following the observation that blood flow was increased in joints of patients with diabetic neuropathy.[4]. This neurovascular theory was based on the sympathetic control of vascular tone, which when compromised by autonomic neuropathy, allows excess blood flow to affected joints leading to inflammation‐induced bone resorption and susceptibility to minor trauma
nerve growth factor (NGF) has been shown to regulate nerve sprouting, activation, and neuropeptide expression and release.[137]. NGF may modulate the vasculature by inducing neural expression of the pro‐angiogenic vascular endothelial growth factor (VEGF),(38) directly activating TrkA receptors on vascular endothelial cells to promote angiogenesis,(39) or potentially even acting directly on osteoblasts.[40] there is evidence that the majority of bone nociceptors express receptors for NGF,(15,37,46,138–146) and blocking signaling through NGF and its receptors reduces pain in animal models of skeletal pathology and prevents inflammation‐induced changes in activity and sensitivity of bone nociceptors
Summary
The field of skeletal neurobiology emerged with a great debate surrounding the relationship between sensory nerve damage and joint disease that began in the mid‐19th century.
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