Abstract Purpose of Review This review aims to highlight the emerging concept that nutrients and metabolites act not merely as energy sources or biosynthetic precursors, but also as instructive signalling molecules in osteoclasts. While much is known about transcriptional and genetic pathways governing osteoclast differentiation and function, comparatively little attention has been given to the role of cellular metabolism and nutrient-sensing mechanisms. This review seeks to categorise key metabolites based on their signalling roles and examine how they influence osteoclastogenesis through metabolic, epigenetic, and inflammatory pathways. Recent Findings Recent studies have demonstrated that nutrients such as glucose, amino acids, and lipids, along with their intermediary metabolites such as succinate, itaconate, α-ketoglutarate (αKG), S-adenosylmethionine (SAM), and acetyl-CoA, regulate osteoclast formation and function by modulating signalling cascades and epigenetic landscapes. These molecules engage nutrient sensors (e.g., aldolase, mTORC1, CPT1) and transcriptional regulators (e.g., NFATc1, PPARs), while also affecting chromatin structure, inflammatory responses, and organelle dynamics. Summary Osteoclast metabolism is tightly linked to cellular fate through nutrient-sensing and metabolite-driven signalling. Elucidating these pathways will reshape our understanding of osteoclast regulation and help identify new metabolic targets for treating bone diseases.
Chandrasekaran et al. (Mon,) studied this question.