Membrane-bound or soluble, mesenchymal or myeloid: which RANKL drives osteoclastogenesis?

Receptor activator of nuclear factor-κB ligand (RANKL) is indispensable for osteoclast differentiation, activation, and bone resorption. While the relative contributions of membrane-bound RANKL (mRANKL) and soluble RANKL were historically debated, evidence from the past decade increasingly establishes mRANKL as the primary driver of osteoclastogenesis. However, a systematic literature synthesis integrating these diverse cellular sources and structural modalities remains lacking. It has also not been systematically defined which cellular sources of RANKL - arising from bone marrow mesenchymal lineage cells or hematopoietic lineage cells - play dominant roles in driving osteoclast activation. Clarifying these distinct forms and sources of RANKL will refine the conceptual framework of osteoclast regulation and provide a mechanistic basis for next-generation antiresorptive therapies that selectively target specific RANKL modalities to achieve more durable skeletal protection.