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.
Highlights
The human skeleton is in a state of constant renewal, in which new bones are generated and old bones are degraded
Low serum (1% fetal bovine serum (FBS)) culture increases the activity of osteoclasts (tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinases (MMPs)-9 expression are upregulated), and the biological functions of other upregulated proteins are mainly enriched in lipid homeostasis, adenosine triphosphate (ATP) hydrolysis coupled proton transport, fatty acid beta-oxidation using acyl-CoA dehydrogenase, translation, TCA cycle and mitochondrial translation, indicating that mitochondrial activity and energy metabolism are significantly increased during the formation of osteoclasts in a low serum culture system [130]
The formation of osteoclasts induced by RANKL depends on increased activity of the TCA cycle and the high ATP levels produced by oxidative phosphorylation, which participate in increasing SAM production, thereby ensuring the inhibition of interferon regulator factor 8 (IRF8, a negative regulator of osteoclastogenesis) methylation by DNA methyltransferase 3a (DNMT3a)
Summary
The human skeleton is in a state of constant renewal, in which new bones are generated and old bones are degraded. Jeong et al found that RANKL-induced osteoclastogenesis was associated with increased activity of lactate dehydrogenase (LDH) to activate glycolysis, a process that relies on increased expression of proton-linked monocarboxylate transporters (MCT1, 2, 3, 5 and 8), excrete lactate from cells produced by increased glycolysis, reduce toxicity and enhance local acidosis to promote bone resorption, and provide positive feedback to stimulate their differentiation [41] These findings were consistent with changes in serum metabolomic profiles in ovariectomized mice during the onset of osteoporosis, in which the serum levels of glucose and lactate were significantly increased [42]. The effect of OXPHOS on osteoclast formation can be further inhibited by the respiratory chain disruptor rotenone, thereby eliminating bone loss due to estrogen deficiency in mice [57, 58]
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