Osteoclast Heterogeneity in Osteoarthritis: From Single-Cell Microenvironments to Program-Specific Therapeutic Opportunities.

Global disability from osteoarthritis (OA) remains a staggering burden, yet disease-modifying pharmacological therapies remain limited. Current evidence supports OA as a whole-joint disease in which subchondral bone remodeling acts as an early and active driver of structural progression and pain. Osteoclasts are key regulators of this process, but clinical trials targeting osteoclast-dependent remodeling have yielded inconsistent results. This translational gap suggests that the traditional view of osteoclasts as a homogeneous, terminally differentiated resorptive population is no longer sufficient. Latest breakthroughs in single-cell and spatial multi-omics have begun to redefine osteoclast biology by revealing heterogeneity across precursor origin, lineage state, functional output, and niche-specific adaptation. In OA, these studies have clarified the osteoclastogenic microenvironment more clearly than the terminal taxonomy of mature osteoclast subsets, thereby shifting the field toward a state-spectrum framework. In this review, we synthesize recent high-resolution evidence to examine how osteoclast-lineage heterogeneity is organized across disease stages and osteochondral microenvironments, and how distinct osteoclast-lineage programs contribute to subchondral remodeling, angiogenic coupling, interface instability, and pain-related pathology. We further discuss how this framework may inform patient stratification, mechanism-matched intervention, and the development of program-specific therapies in OA.