Biology without walls: the novel endocrinology of bone

Abstract

Classical studies of vertebrate physiology have usually been confined to a given organ or cell type. The use of mouse genetics has changed this approach and has rejuvenated the concept of a whole-body study of physiology. One physiological system that has been profoundly influenced by mouse genetics is skeletal physiology. Indeed, genetic approaches have identified several unexpected organs that affect bone physiology. These new links have begun to provide a plausible explanation for the evolutionary involvement of hormones such as leptin with bone physiology. These genetic approaches have also revealed bone as a true endocrine organ capable of regulating energy metabolism and reproduction. Collectively, the body of work discussed below illustrates a new and unconventional role for bone in mammalian physiology.

Figure 1

The sympathetic nervous system (SNS) and CART (cocaine amphetamine regulated transcript) mediate leptin signaling in the brain to the osteoblasts. The SNS inhibits bone formation and favors bone resorption. Following β₂-adrenergic receptor (Adrβ₂) activation in osteoblasts, the sympathetic tone favors expression of RankL, the most powerful osteoclast differentiation factor, and recruits several transcriptional components of the molecular clock, inhibiting bone formation. CART, the second mediator of the leptin regulation of bone mass accrual, also acts on osteoblasts, but by inhibiting RankL expression and bone resorption.

Figure 2

Brain-derived serotonin regulation of bone mass accrual and appetite. Brain-derived serotonin is synthesized by the hydroxylation of tryptophan, a rate-limiting reaction performed by the enzyme tryptophan hydroxylase 2 (Tph2) in the neurons of the dorsal raphe nuclei (DR) and median raphe nuclei (MR) in the brain stem. The axonal projections of serotonergic neurons reach ventromedial hypothalamus (VMH) and arcuate hypothalamus (Arc) neurons of the hypothalamus. Following its binding to the Htr2c receptor in neurons of the VMH nuclei, serotonin favors bone mass accrual, whereas following its binding to the Htr1a and Htr2b receptors in neurons of the Arc nuclei, serotonin favors appetite. The cAMP response element binding (CREB) protein is a crucial transcriptional effector of brain-derived serotonin in Arc neurons. CREB inhibits the expression of the genes encoding tyrosine hydroxylase (Th) and butyrylcholinesterase (Bche) in the VMH and the expression of several genes affecting appetite [melanocortin receptor 4 (Mc4r), pro-opiomelanocortin-α (Pomc-1), neuropeptide VF precursor (Npvf), aspartoacylase 3 (Acy3)] in Arc neurons. Leptin, an adipocyte-derived hormone, directly inhibits serotonin production and its release by the raphe nuclei neurons of the brain stem. The action of leptin is mediated by its receptor, ObRb, which is expressed on these neurons. SNS denotes sympathetic nervous system. Dashed lines indicate that regulation is not a primary signal (but direct); there may be other molecules in between.

Figure 3

Gut-derived serotonin regulation of bone mass accrual. Gut-derived serotonin is synthesized in enterochromaffin cells of the duodenum and acts on osteoblasts through its receptor, Htr1b, and CREB to inhibit osteoblast proliferation.

Figure 4

Endocrine regulation of energy metabolism by bone. Bone mediates such regulation by an osteoblast-specific secreted molecule, osteocalcin, that when undercarboxylated acts as a hormone favoring β-cell proliferation and insulin secretion in the pancreas. The mechanism by which osteocalcin may be activated is regulated in osteoblasts by insulin signaling, which favors osteocalcin bioavailability by promoting its undercarboxylation. In contrast, the sympathetic tone, which is regulated centrally by leptin, decreases osteocalcin bioactivation. SNS denotes sympathetic nervous system.

Figure 5

Endocrine regulation of male fertility by bone. Osteocalcin favors male fertility, increasing testosterone production by Leydig cells of the testes. By binding to a G protein–coupled receptor expressed in the Leydig cells of the testes, osteocalcin, an osteoblast-derived hormone, promotes testosterone production by the testes in a cAMP response element binding (CREB) protein–dependent manner. The dashed arrow indicates that regulation is not a primary signal (but direct); there may be other molecules in between.