Control of bone remodeling by the peripheral sympathetic nervous system

Abstract

The skeleton is no longer seen as a static, isolated, and mostly structural organ. Over the last two decades, a more complete picture of the multiple functions of the skeleton has emerged, and its interactions with a growing number of apparently unrelated organs have become evident. The skeleton not only reacts to mechanical loading and inflammatory, hormonal, and mineral challenges, but also acts of its own accord by secreting factors controlling the function of other tissues, including the kidney and possibly the pancreas and gonads. It is thus becoming widely recognized that it is by nature an endocrine organ, in addition to a structural organ and site of mineral storage and hematopoiesis. Consequently and by definition, bone homeostasis must be tightly regulated and integrated with the biology of other organs to maintain whole body homeostasis, and data uncovering the involvement of the central nervous system (CNS) in the control of bone remodeling support this concept. The sympathetic nervous system (SNS) represents one of the main links between the CNS and the skeleton, based on a number of anatomic, pharmacologic, and genetic studies focused on β-adrenergic receptor (βAR) signaling in bone cells. The goal of this report was to review the data supporting the role of the SNS and βAR signaling in the regulation of skeletal homeostasis.

Fig. 1

The β2AR is the central mediator of SNS signaling in osteoblasts. (a) Activation of the SNS releases catecholamines in the bone which activate osteoblastic β2AR. (b) Signaling is primarily mediated by the stimulatory G-alpha subunit (Gs), which activates adenylyl cyclase, resulting in increased intracellular cAMP, which then activates protein kinase A. (c) The active PKA catalytic subunits can then phosphorylate cytosolic proteins to increase intracellular calcium or translocate to the nucleus (d), where they activate CREB and ATF4. (e) These transcription factors modulate the expression of various genes within the osteoblast that affect its own function as well as the behavior of other cells, e.g., osteoclasts, within the bone. Multiple proteins such as arrestins, phosphodiesterases, and GPCR kinases have been shown to modulate β2AR transduction at different steps within the osteoblast. Additionally, other neurotransmitter receptors that signal through Gq likely also interact with β2AR, signaling transduction within the nucleus. Gi-coupled receptors may be involved in controlling the magnitude of β2AR effects along with other Gs-coupled receptors. (f) β2AR signaling in bone is also controlled centrally by signaling through brain-expressed adrenergic, cannabinoid, and muscarinic receptors, whose activation decreases SNS outflow