Novel Insights into Osteoclast Energy Metabolism

Abstract

Purpose of review: Osteoclasts are crucial for the dynamic remodeling of bone as they resorb old and damaged bone, making space for new bone. Metabolic reprogramming in these cells not only supports phenotypic changes, but also provides the necessary energy for their highly energy-consuming activity, bone resorption. In this review, we highlight recent developments in our understanding of the metabolic adaptations that influence osteoclast behavior and the overall remodeling of bone tissue.

Recent findings: Osteoclasts undergo metabolic reprogramming to meet the energy demands during their transition from precursor cells to fully mature bone-resorbing osteoclasts. Recent research has made considerable progress in pinpointing crucial metabolic adaptations and checkpoint proteins in this process. Notably, glucose metabolism, mitochondrial biogenesis, and oxidative respiration were identified as essential pathways involved in osteoclast differentiation, cytoskeletal organization, and resorptive activity. Furthermore, the interaction between these pathways and amino acid and lipid metabolism adds to the complexity of the process. These interconnected processes can function as diverse fuel sources or have independent regulatory effects, significantly influencing osteoclast function. Energy metabolism in osteoclasts involves various substrates and pathways to meet the energetic requirements of osteoclasts throughout their maturation stages. This understanding of osteoclast biology may provide valuable insights for modulating osteoclast activity during the pathogenesis of bone-related disorders and may pave the way for the development of innovative therapeutic strategies.

Keywords: Bioenergetics; Glycolysis; Mitochondria; Osteoclasts; Oxidative phosphorylation.

Fig. 1

Overview of mitochondrial bioenergetics during osteoclast differentiation and function. Osteoclasts originate from monocyte/macrophage lineage cells, which merge to form specialized multinucleated cells. This process is regulated by M-CSF and RANKL. Upon RANKL signaling, a sequence of events is triggered, activating transcription factors like NFATC1. These factors regulate gene expression to ensure proper osteoclast differentiation and functionality. Given the high energy demands, metabolic adaptations are essential for the development and maturation of osteoclasts. This involves inducing mitochondrial biogenesis through both PGC1β-dependent and independent mechanisms, resulting in an increased number of mitochondria and robust OXPHOS activity to support osteoclastogenesis. Created with Biorender

Fig. 2

How energy metabolism contributes to osteoclast differentiation and function. Energy metabolism plays a crucial role in osteoclast differentiation and function, involving several pathways such as oxidative phosphorylation (OXPHOS), glycolysis, lipid metabolism, glutamine, amino acids (AA), and branched-chain amino acids (BCAAs) metabolism. These pathways are essential for providing the energy needed during the processes of osteoclast differentiation and functional activation. Additionally, both lipid metabolism and amino acid uptake contribute as energy pathways throughout all stages of osteoclast development and function, while the metabolic aspects of the osteomorphs are yet not been fully explored. Created with Biorender