Neurovascular coupling in bone regeneration

www.nature.com/emm REVIEW ARTICLE OPEN Neurovascular coupling in bone regeneration Qizhi Qin 1,6 , Seungyong Lee 2,3,6 ✉ , Nirali Patel4, Kalah Walden4, Mario Gomez-Salazar1, Benjamin Levi5 and Aaron W. James1 ✉ © The Author(s) 2022 The mammalian skeletal system is densely innervated by both neural and vascular networks. Peripheral nerves in the skeleton include sensory and sympathetic nerves. The crosstalk between skeletal and neural tissues is critical for skeletal development and regeneration. The cellular processes of osteogenesis and angiogenesis are coupled in both physiological and pathophysiological contexts. The cellular and molecular regulation of osteogenesis and angiogenesis have yet to be fully defined. This review will provide a detailed characterization of the regulatory role of nerves and blood vessels during bone regeneration. Furthermore, given the importance of the spatial relationship between nerves and blood vessels in bone, we discuss neurovascular coupling during physiological and pathological bone formation. A better understanding of the interactions between nerves and blood vessels will inform future novel therapeutic neural and vascular targeting for clinical bone repair and regeneration. 1234567890();,: Experimental & Molecular Medicine (2022) 54:1844–1849; https://doi.org/10.1038/s12276-022-00899-6 INTRODUCTION Bone tissue is vital for all mammalian species as a living organ system that allows body structure and movement. Bone remodeling maintains bone strength and mineral-calcium homeostasis, and it involves bone cells, including bone-resorbing osteoclasts, bone-forming osteoblasts, osteocytes, and bonelining cells1,2. The skeleton has a rich innervation of both sensory and sympathetic nerve fibers in conjunction with the bone vascular system3–5. Although it has only recently begun to be in the spotlight, the regulatory role of the skeletal, nervous system, including sensory, sympathetic, and parasympathetic nerves, has been examined for many years3–9. Each peripheral nerve fiber subtype has distinct functions within bone10–12. In addition to performing the general roles of nerve fibers, such as providing motor control of muscle fibers, delivering sensory information from the periphery to the central nervous system (CNS), and regulating autonomic functions13, skeletal nerve fibers also provide paracrine stimuli, such as neuropeptide Y (NPY), leptin, calcitonin gene-related peptide (CGRP), and substance P (SP)3,14–16. Moreover, adrenergic receptors and other receptors for neuropeptides residing on osteoblasts and osteoclasts express axon guidance molecules such as semaphorins, netrins, and neurotrophins, which further potentiate nerve ingrowth17,18. Neurotrophins promote the survival of neurons and target innervation by activating the receptors TrkA and p7519. Semaphorins serve as axon guidance molecules during nervous system development20. The growth of peripheral nerve fibers and the initial innervation and neurotransmission into the bone tissue regulate bone remodeling and metabolism21. Furthermore, nerve ingrowth is an essential upstream mediator of endochondral ossification during bone growth22 and intramembranous bone formation during growth and repair7,8,23. These accumulating study findings suggest that the stimuli provided by peripheral afferent neurons represent an essential requirement for proper skeletal growth, homeostasis, and repair7,10,11. Recent studies suggest that the bone vascular system plays a significant role in bone remodeling. Bone marrow arteries and capillaries are essential components of bone multicellular units24–27. The bone vasculature is also important for bone marrow homeostasis28,29. Declines in vascular function and perfusion are predicted to cause reduced bone volume, bone density, osteoblast activity, and increased osteoclastic resorption30–32. Accumulating evidence suggests that the skeletal, nervous, and vascular systems influence one another. Recent works have documented that the majority of sympathetic and parasympathetic nerves are located in association with blood vessels10,33. Moreover, nerves accompanying blood vessels innervate the primary and secondary ossification center during embryonic skeletal development, whereby CGRP-expressed sensory nerves are detected near osteoblasts and the area of high osteogenic activity34,35. However, the extent to which nerve-vessel coupling contributes to improvements in skeletal remodeling and metabolism remains an intriguing unanswered question. As such, this review presents evidence of the roles of neurovascular coupling in bone regeneration, as well as the clinical entity of heterotopic ossification (HO), and summarizes the potential clinical implications of neurovascular coupling in bone tissue. NERVE AND VASCULAR DISTRIBUTION WITHIN THE BONE The skeleton is densely innervated by sensory and sympathetic nerves. Peptidergic sensory nerve fibers are prevalent in the skeletal system of vertebrate species and express the 1 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. 2Department of Physiology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA. 3Department of Physical Education, Incheon National University, Incheon 22012, South Korea. 4Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA. 5Departments of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA. 6These authors contributed equally: Qizhi Qin, Seungyong Lee. ✉email: ; Received: 7 August 2022 Revised: 11 October 2022 Accepted: 11 October 2022 Published online: 29 November 2022 Q. Qin et al. neuropeptides CGRP and SP3,36. The general role of sensory nerves is to transmit internal and external information from the periphery to the CNS for processing of sensory information. The autonomic nervous system (ANS), including sympathetic and parasympathetic nerves, is a part of the efferent peripheral nervous system (PNS) that innervates and regulates all organs and involuntary functions in the body. Sympathetic nerves are abundant in bone and express tyrosine hydroxylase (TH)10,36,37. Both sensory and autonomic nerve fibers in bone are closely linked to bone metabolism and bone remodeling cellular activities. Although sensory and autonomic nerve fibers have been shown to have mixed effects, both types of nerve fibers are strongly associated with blood vessels during skeletal development and bone repair. During development, blood vessels run into the medullary cavity with their accompanying nerves along the shaft within the bone38,39, and the collection of sinusoidal vessels returns to the central nutrient vein along with nerves38,40. In cortical bone, sensory and sympathetic nerve fibers are largely confined to vascularized Haversian canals41. Moreover, CGRP+ and NF200+ sensory nerve fibers are associated with blood vessels located in the Haversian canals, and TH+ sympathetic nerve fibers are (...truncated)