Neuroendocrine and neural control of bone mass in health and disease
Mone Zaidi, Se-Min Kim, Vitaly Ryu, Daria Lizneva, Terry F. Davies, Clifford J. Rosen, Tony Yuen, Andrea Giustina
Mone Zaidi, Se-Min Kim, Vitaly Ryu, Daria Lizneva, Terry F. Davies, Clifford J. Rosen, Tony Yuen, Andrea Giustina
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Neuroendocrine and neural control of bone mass in health and disease

Abstract

Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteoblasts, results in bone loss, which, in turn, is associated with debilitating conditions, including osteoporosis and metastatic bone disease. The past decade has revealed vital new insights into the role of the central nervous system in skeletal regulation. These studies have led to a better understanding of physiologic circuitry, enabled us to revisit disease pathophysiology, and in doing so, prompted the creation of candidate therapeutics. The central neural control of bone is exerted through two arms — an amplitude-modulated (AM) neurohormonal arm that relies on changes in circulating levels of anterior and posterior pituitary hormones, which act on bone directly, and a frequency-modulated (FM) arm that arises from changes in the firing frequency of sympathetic, parasympathetic, and sensory nerves that innervate bone. Here, we review the medical consequences arising from the dysfunction of the AM and FM arms, as well as studies that have unmasked promising therapeutic targets.

Authors

Mone Zaidi, Se-Min Kim, Vitaly Ryu, Daria Lizneva, Terry F. Davies, Clifford J. Rosen, Tony Yuen, Andrea Giustina

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Figure 1

Pituitary hormones directly regulate bone cells — the AM arm.

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Pituitary hormones directly regulate bone cells — the AM arm. (A) Anteri...
(A) Anterior pituitary hormones act on both osteoblasts and osteoclasts via G protein–coupled receptors and, indirectly, through cytokines. FSH interacts with FSHRs on osteoclasts and on macrophages; the latter release TNF-α, which, in turn, promotes bone resorption. FSH also acts on FSHRs on osteoblast precursors to suppress their differentiation. TSH promotes bone formation via Wnt5a, while inhibiting osteoclastic bone resorption by downregulating the NF-κB pathway. A TSH variant, TSHβv, released from immune cells also acts on the same TSHRs on bone cells. Osteoblastic MC2R activation by ACTH upregulates VEGF. GH and IGF-1 promote bone remodeling via JAK2/STAT5b and IRS-1, respectively. Locally derived IGFBP scavenges IGF-1. (B) The posterior pituitary nonapeptide oxytocin (OXT) increases bone turnover by acting on osteoblast OXTRs to promote bone formation through BMP2 and osterix (OSX) upregulation. Osteoclastogenesis is also enhanced via the upregulation of AKT and ERK1/2 signaling, which, in turn, facilitates maternal-fetal calcium transfer during pregnancy when serum OXT levels are high. Arginine vasopressin receptor 1a (AVPR1a) opposes OXT action to inhibit bone formation. MSC, mesenchymal stem cell; MC2R, melanocortin 2 receptor; IRS, insulin receptor substrate; IGFBP, insulin growth factor–binding protein; OPG, osteoprotegerin; Opn, osteopontin; Col1a1, collagen 1α1.