Hypothalamic regulation of bone

Abstract

On initial inspection, bone remodeling, the process whereby the skeleton adapts through time, appears to be relatively simple. Two cell types, the bone-forming osteoblasts and the bone-resorbing osteoclasts, interact to keep bone mass relatively stable throughout adult life. However, the complexity of the regulatory influences on these cells is continuing to expand our understanding of the intricacy of skeletal physiology and also the interactions between other organ systems and bone. One such example of the broadening of understanding in this field has occurred in the last decade with study of the central, neural regulation of bone mass. Initial studies of an adipose-derived hormone, leptin, helped define a direct, sympathetic pathway involving efferent neural signals from the hypothalamus to receptors on the osteoblast. Since the leptin-mediated pathway has been continuously modified to reveal a complex system involving neuromedin U, cocaineand amphetamine-related transcript and serotonin interacting within the hypothalamus and brainstem to regulate both bone formation and resorption in cancellous bone, a number of other systems have also been identified. Neuropeptide Y, acting through hypothalamic Y2 receptors, is capable of skeleton-wide modulation of osteoblast activity, with important coordination between body weight and bone mass. Cannabinoids, acting through central cannabinoid receptor 1 and bone cell cannabinoid receptor 2 receptors, modulate osteoclast activity, thereby identifying pathways active on both aspects of the bone remodeling process. This review explores the key central pathways to bone and explores the complexity of the interactions being revealed by this emergent field of research. Journal of Molecular Endocrinology (2010) 45, 175-181 Function of hypothalamusThe brain has long been appreciated as a pivotal regulator of homeostasis in peripheral tissues, including the skeleton. There is now clear evidence for crosstalk between the brain and bone through two distinct routes. The first pathway comprises welldefined hormonal signals arising from neuroendocrine neurons of the hypothalamus and subsequently processed within the pituitary. The second pathway consists of efferent neuronal discharges originating from the hypothalamus and processed through the brainstem. The hypothalamus, with its semipermeable blood-brain barrier, is thus one of the most powerful regulatory regions within the body, integrating signals not only from peripheral tissues but also from within the brain itself. These direct, neural pathways represent an emergent area of study that is identifying novel regulatory axes between the brain and the cells of bone. Moreover, this work is also providing insights into regulatory connections involving skeletal tissue, which are proving to be unexpected, thereby outlining a level of interconnectedness that has been previously unappreciated. This review examines the expanded understanding of the central, neural outputs to bone metabolism and remodeling.

Associations Between Liver Function, Bone Turnover Biomarkers and Adipokines in Older Patients With Hip Fracture

“…These findings are in contrast with the widespread (based mainly on animal studies) view that leptin acting primarily through the centrally (hypothalamus and brainstem) mediated pathways suppresses bone formation [14,71,72], but are in accord with some, but not all [34,44,[73][74][75][76], clinical studies that reported a positive association between serum leptin and OC levels [77,78] and with experiments showing that peripheral leptin increases osteoblast proliferation, differentiation and activity, inhibits osteoclast activity and bone resorption, increasing bone mass [79][80][81]. Furthermore, a meta-analysis (59 studies) found that leptin was positively associated with bone mineral density (BMD) and high levels of leptin were predictive of lower risk of fractures [82].…”

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

“…Discovery of the scope and strength of neural influences upon skeletal tissue has been an important advance in bone biology in recent years (Driessler and Baldock, 2010). Further expanding these unique neuro/skeletal relationships, here we identify a novel interaction between the opioid system and bone demonstrating an inhibitory action of dynorphins on skeletal tissue, acting through kappa opioid receptors.…”

Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice

“…(reviewed in refs (24) and (25) ). Leptin interacts directly or indirectly with these systems, thereby accounting for some of the differential effects reported for leptin in different bone compartments.…”