BoneKEy-Osteovision | Commentary
Boneheads meet brainheads: The central control of bone mass
Gordon J Strewler
Joel K Elmquist
DOI:10.1138/2002053
Commentary on: Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest. 2002 Apr;109(7):915-21.
The notion that the central nervous system (CNS) contributes to the regulation of bone mass was a revelation to the bone field. The original observation by Ducy et al. was that ob/ob mice have high bone mass (). Ob/ob mice become massively obese because of deficiency in the adipocyte hormone leptin. The increase in bone mass could not be explained either by their profound obesity itself or by the other manifestations of the leptin deficiency syndrome - hypercorticism, hypogonadism, or decreased somatotropic activity. Infusion of leptin into the 3rd cerebral ventricle of ob/ob mice markedly lowered bone mass (). Although leptin may have receptors and various actions in bone itself (), central infusions of leptin at the rates used in these experiments is unlikely to produce effects in the periphery. Thus, leptin had its effects to reduce bone mass via actions in the CNS. If confirmed, these results thus support a model that leptin acts within the brain to regulate bone mass by a novel mechanism, either neural or humoral.
The rapidly unfolding story of appetite and satiety provides the neuroendocrine context for the reported effects of leptin on bone mass (). Two neuropeptide systems are now understood as downstream targets of leptin to mediate its effects on the regulation of appetite and metabolism. Both have now been implicated independently in the CNS control of bone mass.
Before the discovery of leptin it was already established that neuropeptide Y (NPY) is a potent stimulator of food intake. NPY is a widely expressed neuropeptide in the CNS. A prominent population of NPY neurons resides in the arcuate nucleus, and these cells have been implicated in the control of energy balance. For example, NPY levels in the arcuate nucleus of the hypothalamus are increased by fasting rats as well as in ob/ob mice (). The NPY neurons in the arcuate possess leptin receptors and are thought to be directly inhibited by leptin (). Administration of leptin to fasting rats or ob/ob mice suppresses overexpression of NPY. Moreover, deficiency of NPY partially rescues ob/ob mice from obesity, placing NPY neurons downstream of leptin but implying the existence of another effector pathway ().
Another identified pathway is the melanocortin system represented by α-melanocyte-stimulating hormone (α-MSH), a product of the pro-opiomelanocortin (POMC) gene and an agonist of melanocortin receptors (). Mutations that result in a loss of function in POMC or in the melanocortin 4 receptor (MC4R) produce obesity in humans and mice. Leptin receptors are expressed by POMC neurons of the arcuate nucleus, and leptin upregulates POMC mRNA. Moreover, leptin directly depolarizes POMC neurons, presumably resulting in release of α-MSH from nerve terminals in target sites (). The system also has a powerful inhibitory arm. The agouti protein, a naturally occuring antagonist of melanocortin receptors, causes marked obesity when overexpressed in the hypothalamus. Though the agouti protein is not normally expressed in the brain, an endogenous antagonist, agouti-related protein (AgRP) was identified in neurons of the arcuate nucleus of the hypothalamus. AgRP is coexpressed in NPY neurons in the arcuate nucleus and thus is inhibited by leptin. An emerging model predicts that leptin should induce the release of α-MSH and inhibit AgRP release, resulting in a net increase in activity of the MC4R. In contrast, when leptin levels fall during fasting there is a net inhibition of MC4R neurons by AgRP (acting directly at the α-MSH receptor) and by NPY (acting though one of its Gi-coupled receptors).
A model of leptin action in the arcuate nucleus is shown in Fig 1. This diagram illustrates that components of the system for control of food intake are present in the arcuate nucleus, but MC4R receptors are widely distributed in other brain regions, including regions that control the autonomic nervous system (sympathetic preganglionic neurons in the intermediolateral column in the spinal cord and parasympathetic preganglionic neurons in the dorsal nucleus of the vagus in the brainstem). NPY neurons also project to brain stem areas where autonomic activity is regulated.
Mutations that inactivate the MC4R gene produce a syndrome of obesity and hyperinsulinemia in humans (). Interestingly, these individuals have accelerated childhood bone growth and a 1.0 to 4.9 year advance in bone age. (Other obesity syndromes are also associated with advancement in bone age.) Affected individuals also have increased bone mineral density (Z score +2.32), but this could be a consequence, at least in part, of their obesity (mean BMI 37.5). Targeted deletion of the MC4R also produces obesity in the mouse (), but the detailed bone phenotype of the MC4R(-/-) mouse has yet to be reported.
Additional evidence of a hypothalamic system that regulates bone mass comes from the demonstration that central infusions of NPY produce bone loss similarly to infusion of leptin (). This makes it clear that, in contrast to obesity due to leptin deficiency (Fig 1), the high hypothalamic NPY levels that are seen in leptin deficiency are not simple effectors of bone gain. NPY effects are mediated by at least five different hypothalamic receptors. To elucidate the role of the NPY system in the regulation of bone mass, Baldock et al. made targeted deletions of one of the NPY receptors, Y2. They report that Y2(-/-) mice have a two-fold increase in trabecular bone volume (). The receptor was deleted in the germline by classical gene targeting techniques and also specifically in the hypothalamus by injection of adenovirus expressing recombinant Cre-recombinase directly into the arcuate nucleus of Y2lox/lox mice. The use of an adenovirus to deliver Cre-recombinase to specific brain regions permits deletion of genes in regions for which there is no specific promoter available for targeting. In this case, specific targeting of Y2 in the arcuate nucleus essentially reproduced the phenotype of the germline deletion of Y2.
Y2 receptors are notably present on NPY neurons themselves and are thought to act as inhibitory autoreceptors in an autocrine negative feedback loop (Fig 1). In keeping with this idea, Baldock et al. report that deficiency of Y2 leads to increased expression of NPY in the arcuate nucleus, similar to leptin deficiency. Moreover, the high bone mass phenotype was not exaggerated in Y2(-/-), ob/ob double knockout mice, consistent with leptin and Y2 operating in the same pathway. It is intriguing to speculate what the bone mass effects of leptin infusion would be in Y2(-/-) mice, but this experiment was not done.
Taken together, these studies present an interesting model of hypothalamic control of bone density. However, the relationship between leptin effects on bone mass and NPY remains to be completely clarified. It is likely that NPY receptors other than Y2 are involved in the effects of both leptin and NPY infusion on bone mass. The specific receptors involved and the anatomic loci of these actions within the CNS need to be identified. Nonetheless, the notion that bone mass is centrally regulated represents a paradigm shift () and is supported by findings that the NPY system and MC4Rs regulate bone mass. Moreover, both systems regulate the activity of the autonomic nervous system, which now seems to be an attractive candidate as the pathway from brain to bone.
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