The contribution of bone to whole-organism physiology

Abstract

The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiology can broaden the functions of a given organ, reveal connections of this organ with others such as the brain, pancreas and gut, and shed new light on the pathogenesis of degenerative diseases affecting multiple organs.

Figure 1 ∣. Leptin co-regulates appetite and bone mass.

Leptin signals through its receptor (Lepr), expressed in serotonin-producing neurons of the raphe nuclei in the brainstem, decreasing the expression of tryptophan hydrxylase 2 (Tph2), the gene encoding the initial enzyme for serotonin biosynthesis. Signalling by Lepr requires Jak2 and is negatively regulated by Socs3. Serotonin-producing neurons of the raphe nuclei project to the ventromedial (VMH) and the arcuate (Arc) hypothalamic nuclei. Serotonin signalling in VMH neurons decreases the activity of the sympathetic nervous system (SNS), an inhibitor of bone mass accrual. In Arc neurons, serotonin signalling has anti-anorexigenic effects.

Figure 2 ∣. Osteocalcin, a bone-derived multifunctional hormone.

Undercarboxylated osteocalcin stimulates insulin secretion and β-cell proliferation in the pancreas, energy expenditure by muscle, and insulin sensitivity in adipose tissue, muscle and liver. In addition, it promotes male fertility by stimulating testosterone synthesis in Leydig cells of the testis through the activation of its receptor, GPRC6A, in these cells.

Figure 3 ∣. A feedforward loop links insulin, bone resorption and osteocalcin activity.

Insulin signalling in osteoblasts decreases the expression of Opg. The decrease in the ratio of osteoprotegerin (OPG) to receptor activator of nuclear factor–κB ligand (RANKL) increases bone resorption by osteoclasts. The acidic pH (4.5) in resorption lacunae decarboxylates (that is, activates) osteocalcin (GLA-OCN) stored in the bone extracellular matrix. Undercarboxylated active osteocalcin (GLU13-OCN) then stimulates insulin secretion by the β-cells of the pancreatic islets and promotes insulin sensitivity in peripheral organs. ECM, extracellular matrix; InsR, insulin receptor.

Figure 4 ∣. Interactions between the gastrointestinal tract and bone mass.

Stomach acidity (low pH) is required for the proper absorption of calcium (Ca²⁺) and is, therefore, essential to maintain normal levels of serum calcium. Serum calcium, in turn, negatively regulates secretion from the parathyroid gland of PTH, a hormone that stimulates osteoclast differentiation and bone resorption. Bone resorption by osteoclasts also occurs at low pH and contributes to the maintenance of serum calcium. Peripheral serotonin is produced by the duodenum and inhibits bone formation by osteoblasts, whereas dietary intake of amino acids (proteins) favours collagen synthesis by osteoblasts.