Osteometabolism: Metabolic Alterations in Bone Pathologies

Abstract

Renewing interest in the study of intermediate metabolism and cellular bioenergetics is brought on by the global increase in the prevalence of metabolic illnesses. Understanding of the mechanisms that integrate energy metabolism in the entire organism has significantly improved with the application of contemporary biochemical tools for quantifying the fuel substrate metabolism with cutting-edge mouse genetic procedures. Several unexpected findings in genetically altered mice have prompted research into the direction of intermediate metabolism of skeletal cells. These findings point to the possibility of novel endocrine connections through which bone cells can convey their energy status to other metabolic control centers. Understanding the expanded function of skeleton system has in turn inspired new lines of research aimed at characterizing the energy needs and bioenergetic characteristics of these bone cells. Bone-forming osteoblast and bone-resorbing osteoclast cells require a constant and large supply of energy substrates such as glucose, fatty acids, glutamine, etc., for their differentiation and functional activity. According to latest research, important developmental signaling pathways in bone cells are connected to bioenergetic programs, which may accommodate variations in energy requirements during their life cycle. The present review article provides a unique perspective of the past and present research in the metabolic characteristics of bone cells along with mechanisms governing energy substrate utilization and bioenergetics. In addition, we discussed the therapeutic inventions which are currently being utilized for the treatment and management of bone-related diseases such as osteoporosis, rheumatoid arthritis (RA), osteogenesis imperfecta (OIM), etc., by modulating the energetics of bone cells. We further emphasized on the role of GUT-associated metabolites (GAMs) such as short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), indole derivates, bile acids, etc., in regulating the energetics of bone cells and their plausible role in maintaining bone health. Emphasis is importantly placed on highlighting knowledge gaps in this novel field of skeletal biology, i.e., "Osteometabolism" (proposed by our group) that need to be further explored to characterize the physiological importance of skeletal cell bioenergetics in the context of human health and bone related metabolic diseases.

Keywords: Osteometabolism; bone cells; bone pathologies; gut-associated metabolites (GAMs); metabolism.

Figure 1

Activation of PPARγ controls bone cell homeostasis: Activation of PPARγ promotes the differentiation of HSCs to mature osteoclasts by inducing the expression of osteoclastogenic genes such as cathepsin K (Ctsk) and c-Fos. In response to ligand, activated PPARγ forms a heterodimeric complex with the retinoic X receptor alpha (RXRα) that further recruits the co-activators such as PGC-1β and thus controls the expression of osteoclastogenic genes. In addition, PPARγ inhibits the differentiation of MSCs into osteoblasts and promotes MSCs differentiation into adipocytes.

Figure 2

Metabolic pathways in Osteoblasts: In response to the Wnt ligand, BMPs and TGFβ, MSCs differentiate into mature osteoblasts. Glut1 controls the uptake of glucose in osteoblast precursors that via inhibiting the phosphorylation of AMP-activated protein kinase (AMPK) suppress the phosphorylation of E3 ubiquitin ligase (SMURF1) that in turn reduces the ubiquitination of Runx2 and thus prevents the proteasomal degradation of Runx2. In addition, glucose uptake also activates the mTORC1 and induces the synthesis of collagen. The uptake of glutamine via the SLC1A5 receptor activates mTORC1 which further inhibits GSK3β by activating the mTORC2 and thus suppresses the degradation of Runx2. In addition, osteoblast precursors express lipid and soluble fat receptors such as the low-density lipoprotein receptor (LDLR), LDL receptor-related protein-1 (LRP-1), CD36, scavenger receptor class B member 1 “Scarb-1”, and the free fatty acid receptor (FFAR-4) that upon ligand binding induces the generation of acetyl-COA that feeds into the TCA cycle to stabilize the expression of osteoblasts genes such as Runx2 and thus enhances the mineralization ability of osteoblasts.

Figure 3

Metabolic pathways in Osteoclasts: In response to M-CSF and RANKL, HSCs differentiate into mature osteoclasts. Glut1 controls the uptake of glucose in osteoclast precursors that produce lactate via anaerobic respiration and under aerobic respiration produce pyruvate that undergoes TCA, OXPHOS and promotes ATP generation and thus induces osteoclastogenesis and bone resorption. RANK-RANKL signaling induces the activation of a peroxisome proliferator-activated receptor-gamma coactivator 1β (PGC1β) that, by promoting mitochondrial biogenesis in osteoclasts precursors, further induces its differentiation. In response to iron, the generation of a reactive oxygen species (ROS) stimulates the expression of PGC1β and thus promotes osteoclast differentiation and bone resorption.

Figure 4

Hypoxia promotes osteoclast differentiation and bone resorption: Osteoclastogenesis is accelerated in hypoxic circumstances. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) promote the fusion of osteoclasts. HIF-2α also promotes the expression of TRAF6, enhancing the activation of the NF-κB signaling pathway and maturation of osteoclasts. In addition, hypoxia promotes the activation of NF-κB by reducing the expression of osteoprotegerin (OPG). HIF-1α and HIF-2α, as well as the inhibition of the prolyl hydroxylase domain (PHD), stimulate the production of pro-resorptive genes. Additionally, HIF-1 α is important in promoting glycolytic activity either directly or via negatively regulating the expression of the copper metabolism domain containing 1 (COMMD1) gene. Hypoxia also activates RANK-RANKL signaling that, by promoting the expression of elongation transcription factor (E2F), induces glycolysis and thus enhances the differentiation of osteoclasts along with its induced bone resorption activity.

Figure 5

Bone cells and global energy metabolism: Osteoblasts release OCN, which is C-carboxylated (GlaOCN), into the bone extracellular matrix (ECM). Osteoclasts form bone resorption lacunae having acidic pH (~4.5) to aid the decarboxylation of GlaOCN to GluOCN. GluOCN enters into the circulation and acts as an endocrine hormone. GluOCN controls global energy metabolism by regulating the uptake of glucose in the muscles, production of insulin in the pancreas, enhancement in the adiponectin expression in the adipose tissues, promoting the proliferation of β-cell in the pancreas. In addition to controlling energy metabolism, OCN regulates the synthesis of testosterone by the Leydig cells and thus controls male fertility. It also facilitates the development of the hippocampus region of the brain. Strikingly, in the tissues like the testis, muscles, and pancreas, OCN regulates its endocrine functions by binding to the G-protein coupled receptor (GPRC6A). However, how OCN acts on the brain, liver, and adipose still need investigation.

Figure 6

Osteometabolism (Metabolism of Bone Cells): In precursors form, osteoclast and osteoblast cells obtain maximum energy from oxidative phosphorylation whereas in mature form these bone cells obtain energy predominantly from glycolysis.