The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis

Abstract

In recent decades, the mechanism underlying bone metabolic disorders based on energy metabolism has been heavily researched. Bone resorption by osteoclasts plays an important role in the occurrence and development of osteoporosis. However, the mechanism underlying the osteoclast energy metabolism disorder that interferes with bone homeostasis has not been determined. Bone resorption by osteoclasts is a process that consumes large amounts of adenosine triphosphate (ATP) produced by glycolysis and oxidative phosphorylation. In addition to glucose, fatty acids and amino acids can also be used as substrates to produce energy through oxidative phosphorylation. In this review, we summarize and analyze the energy-based phenotypic changes, epigenetic regulation, and coupling with systemic energy metabolism of osteoclasts during the development and progression of osteoporosis. At the same time, we propose a hypothesis, the compensatory recovery mechanism (involving the balance between osteoclast survival and functional activation), which may provide a new approach for the treatment of osteoporosis.

Keywords: bone homeostasis; bone resorption; energy metabolism; osteoclasts; osteoporosis.

Figure 1

From the perspective of energy metabolism, over-differentiation of osteoclasts leads to osteoporosis. Multifactorial regulation of osteoclastogenesis is accompanied by an increased mitochondrial number and increased cellular respiration and ATP production. The orange line represents a positive feedback mechanism. ATP, adenosine triphosphate; ERR, estrogen receptor-associated receptors; M-CSF, macrophage colony stimulating factor; OXPHOS, oxidative phosphorylation; PGC-1β, peroxisome proliferator-activated receptor gamma coactivator-1β; RANK, receptor activator of NF-kB; RANKL, receptor activator of nuclear factor kappa-B ligand; ROS, reactive oxygen species; TCA cycle, tricarboxylic acid cycle.

Figure 2

From the perspective of energy metabolism, abnormal osteoclast proliferation, senescence, apoptosis and autophagy phenotypes lead to osteoporosis. The imbalance in homeostasis between osteoclast survival and the bone resorptive capacity is a key factor contributing to the development of osteoporosis. ATP, adenosine triphosphate; mtDNA, mitochondrial DNA. –, negative control; +, positive control.

Figure 3

Hypothesis of the compensatory recovery mechanism of osteoclasts. (A) Based on proapoptotic BIM and anti-apoptotic BCL-xL, an imbalance between osteoclast survival and bone resorptive capacity occurs in OP. (B) The disruption of homeostasis between the enhancement of bone resorption activity mediated by hypoxia and the inhibition of ROS on the survival of osteoclasts promotes the occurrence of osteoporosis. (C) RANKL-mediated oxidative stress results in an imbalance between osteoclast survival and bone resorption capacity. ATP, adenosine triphosphate; BCL-xL, B-cell lymphoma-extra large; BIM, BCL-2-like protein 11; HIF-1, hypoxia-induced factor-1; OP, osteoporosis; ROS, reactive oxygen species; RANKL, receptor activator of nuclear factor kappa-B ligand; SOD2, superoxide dismutase 2.