Cell signaling and transcriptional regulation of osteoclast lineage commitment, differentiation, bone resorption and diseases.

Osteoclasts are bone-resorbing cells that play a central role in normal bone remodeling and contribute to bone loss associated with pathological conditions such as osteoporosis, osteoarthritis, rheumatoid arthritis, periodontal disease, and bone metastases of cancer. The commitment, differentiation, and function of osteoclasts depend on the establishment of specific gene expression patterns orchestrated through a network of transcription factors, which are sequentially activated by osteoclastogenic signals. This review provides an updated overview of the roles of key signaling pathways (e.g., RANKL signaling, NF-κB signaling and Gα13 signaling), transcription factors (e.g., PU.1, C/EBP-α, NFATc1 and IRF8), cytokines (e.g., TNF-α, IL-1β and IL-6), and epigenetic regulators (e.g., DNMT3a, EZH2 and ASXL1) in osteoclast lineage commitment, differentiation and bone resorption under both physiological and pathological inflammatory conditions, along with insights from corresponding mouse models. We described the mechanism by which osteoclast-mediated bone resorption occurs through extracellular acidification driven by osteoclast-specific proton pump subunits (e.g., ATP6i and ATP6v0d2), followed by matrix protein degradation mediated by cathepsin K and MMP-9. Additionally, this review examines the interplay among molecular mechanisms that regulate osteoclast differentiation and activation under pathological and inflammatory conditions, elucidates their roles in osteoclast hyperactivation-related human diseases, and provides a comprehensive framework for understanding these processes. Finally, it underscores potential novel therapeutic strategies for osteoclast-related skeletal lytic diseases and highlights perspectives for future investigations.