Metabolic reprogramming in osteoclasts

Abstract

Osteoclasts are bone-resorbing cells that play an essential role in the remodeling of the bone. Defects in osteoclasts thus result in unbalanced bone remodeling, leading to numerous pathological conditions such as osteoporosis, bone metastasis, and inflammatory bone erosion. Metabolism is any process a cell utilizes to meet its energetic demand for biological functions. Along with signaling pathways and osteoclast-specific gene expression programs, osteoclast differentiation activates metabolic programs. The energy generated from metabolic reprogramming in osteoclasts not only supports the phenotypic changes from mononuclear precursor cells to multinuclear osteoclasts, but also facilitates bone resorption, a major function of terminally differentiated, mature osteoclasts. While oxidative phosphorylation is studied as a major metabolic pathway that fulfills the energy demands of osteoclasts, all metabolic pathways are closely interconnected. Therefore, it remains important to understand the various aspects of osteoclast metabolism, including the roles and effects of glycolysis, glutaminolysis, fatty acid synthesis, and fatty acid oxidation. Targeting the pathways associated with metabolic reprogramming has shown beneficial effects on pathological conditions. As a result, it is clear that a deeper understanding of metabolic regulation in osteoclasts will offer broader translational potential for the treatment of human bone disorders.

Keywords: Metabolic reprogramming; Metabolism; Osteoclasts.

Figure 1.. Mitochondria play an important role in osteoclast differentiation.

(A) Osteoclasts are formed by the fusion of monocytic osteoclast precursors after precursor cell exposure to osteoclastogenic signals such as RANKL. During differentiation, osteoclast precursor cells undergo rapid and extensive changes in shape and size to generate multinuclear cells. In fully differentiated mature osteoclasts, mitochondria are formed in a complex tubular network, increasing in size and full of cristae. Mitochondria biogenesis is induced by PGC1β-dependent and independent mechanism. (B) Electro transport chain (ETC) reactions occur in the inner membrane of mitochondria and ETC is the site of oxidative phosphorylation. Electron [58] transfer couples with the transfer of protons (H⁺), leading to generating proton gradient. NADH and FADH₂ : reduced electro carriers; Q: ubiquinone; C; cytochrome C. (C) RANKL signaling induces PGC1β, which is involved in mitochondria biogenesis, and the MYC-ERRα axis to regulate ETC gene expression and OXPHOS.

Figure 2.. Osteoclasts increase glycolytic flux.

Extracellular glucose crosses plasma membrane via GLUT1. Glycolysis converts glucose to pyruvate, producing two molecules of ATP in the process. Pyruvate then enters mitochondria and the production of most mitochondrial ATP takes place through a series of reactions known as TCA cycle (tricarboxylic acid cycle). HIF1 regulates the expression of glycolytic genes including GLUT1 and LDHA. TCA cycle intermediate citrate is used for lipid synthesis and acetyl-CoA is converted into fatty acid by fatty acid synthesis and cholesterol. Glutamine is converted into alpha-ketoglutarate (α-KG).