Bone Cell Bioenergetics and Skeletal Energy Homeostasis

Abstract

The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease.

FIGURE 1.

The cells of bone. Bone is formed and remodeled by the concerted actions of three major cell types. Bone resorption is performed by the osteoclasts, a multinucleated cell that differentiates from hematopoietic precursors in the monocyte macrophage lineage under the control of RANK ligand (RANKL) signaling. Osteoblasts are bone-forming cells, which descend from mesenchymal stromal cells and differentiate into mature, cuboidal, cells that synthesize bone matrix and mineralize it. A proportion of mature osteoblasts further differentiates into osteocytes and is entombed in the skeletal matrix. Osteocytes produce RANKL and sclerostin, a negative inhibitor of Wnt signaling. They are believed to serve as mechanosensors that transduce mechanical stimuli to promote bone formation.

FIGURE 2.

Energy substrates and intermediary metabolic pathways. The primary energy substrate for the generation of carbon skeletons is absorbed glucose, which is converted to acetyl coenzyme A (CoA) through glycolysis and then ATP through the TCA cycle and subsequent oxidative phosphorylation. Proteins and amino acids as well as fatty acids and ketones can all be utilized by the body to produce acetyl CoA as required. Interactions between these pathways are widespread and routine (double ended arrows), allowing the production of energy as dictated by the fuel sources available.

FIGURE 3.

Regulation of osteoblast function by the adipokines leptin and adiponectin. A: leptin produced by adipocytes exerts direct effects on the osteoblast lineage, as well as indirect effects via the central nervous system. Osteoprogenitors within the appendicular skeleton express Lepr, and its ablation increases bone volume secondary to an increased mineral apposition rate and increased numbers of marrow progenitors. Within the brain, leptin inhibits serotonin production, which in turn increases the sympathetic tone and leads to the activation of β2-adrenergic receptors expressed by osteoblasts. B: adipose-derived adiponectin exhibits age-related effects on osteoblast function. In contrast to the mitogenic effects of adiponectin observed in vitro, in vivo studies suggest the hormone suppresses osteoblast proliferation and bone acquisition in young mice. As mice age, adiponectin acts within the brain to suppress the actions of leptin and reduce the sympathetic tone.

FIGURE 4.

The insulin-osteocalcin endocrine loop. Recent studies suggest the existence of a bone-pancreas endocrine loop that allows the osteoblast to participate in the regulation of glucose metabolism. By activating the IR on osteoblasts, insulin regulates the production of undercarboxylated osteocalcin (Glu-OCN), which regulates insulin production in the pancreas and insulin sensitivity in peripheral tissues like fat. Two mechanisms of insulin-dependent control of Glu-OCN have been proposed. By inducing FoxO1 nuclear export, insulin reduces the expression of OPG and thereby stimulates bone turnover and the decarboxylation of matrix-bound carboxylated osteocalcin (Gla-OCN). IR signaling in the osteoblast suppresses the expression of the Runx2 inhibitor, Twist2, and promotes Runx2-mediated osteocalcin production.

FIGURE 5.

Hypothetical model for coupling of developmental and bioenergetic programs in osteoblasts. The distinct phases of the osteoblast life cycle have markedly different metabolic requirements. Replicating preosteoblasts depend on Glut1-mediated glucose transport and glycolytic metabolism which is controlled by Runx2 and HIF-1 signaling. Mature mineralizing osteoblasts diversify fuel sources to burn both glucose (facilitated by Glut4) and fatty acids and maximize energy production by engaging oxidative phosphorylation through the TCA cycle. Wnt/Lrp5 signaling appears to be required for oxidation of fatty acids. The preferred fuel and bioenergetic program of the osteocytes embedded in mineralized bone remains unknown.