RANK‐Fc: A therapeutic antagonist for RANK‐L in myeloma

Severe bone destruction due to inappropriate osteoclastogenesis is a prominent feature of multiple myeloma (MM). MM increases bone loss by disrupting the checks that normally control signaling by receptor activator of nuclear factor κB ligand (RANK‐L, also called TRANCE [tumor necrosis factor‐related, activation‐induced cytokine], osteoprotegerin ligand [OPG‐L], osteoclast differentiation factor [ODF], and tumor necrosis factor superfamily member 11 [TNFSF11]), a TNF‐family cytokine required for osteoclast differentiation and activation. RANK‐L binds to its functional receptor RANK (TNF receptor superfamily member 11a [TNF RSF11a]) to stimulate osteoclastogenesis. Osteotropic cytokines regulate this process by controlling bone marrow stromal expression of RANK‐L. Further control over osteoclastogenesis is maintained by regulated expression of osteoprotegerin (OPG, also called osteoclastogenesis inhibitory factor and TNFRSF11b), a soluble decoy receptor for RANK‐L. In normal bone marrow, abundant stores of OPG in stroma, megakaryocytes, and myeloid cells provide a natural buffer against increased RANK‐L. MM disrupts these controls by increasing expression of RANK‐L and decreasing expression of OPG. Concurrent deregulation of RANK‐L and OPG expression is found in bone marrow biopsies from patients with MM but not in specimens from patients with non‐MM hematologic malignancies.