The high rate of bone resorption in multiple myeloma is due to RANK (receptor activator of nuclear factor-kappaB) and RANK Ligand expression.
The excessive bone resorption observed in multiple myeloma may be due to the production of several osteoclast-activating factors either by the myeloma cells themselves or by the bone marrow microenvironment. These factors could act primarily via a common final pathway involving the recently-described members of the TNF receptor-ligand family: RANKL (Receptor Activator of NK-kappaB Ligand) and its corresponding RANK receptor that play a crucial role in osteoclast differentiation and activation, and osteoprotegerin (OPG), the physiological inhibitor of RANKL. RANKL expression by stromal cells is increased in myeloma and is associated with a concomitant decrease in OPG expression. This increase in RANKL-OPG ratio correlates with the extent of the myeloma bone disease. The RANKL-OPG imbalance could play a decisive role in the lytic bone lesions in myeloma, and this possibility is reinforced by several in-vivo studies that have assessed the effects of administering RANKL inhibitors in murine myeloma models. Treatment with either OPG: Fc or RANK: Fc decreased myeloma osteolysis in these models. RANKL blockade is also currently being evaluated in malignant osteolysis in humans. A therapeutic approach targeting the RANKL-RANK signaling pathway could be of great value, as RANKL inhibitors are potent anti-resorptive agents, affecting both myeloma-induced bone resorption and the tumor burden.
Roux
Sophie
S
Department of Rheumatology, Sherbrooke University, Sherbrooke, PQ Canada.
Mariette
Xavier
X
D000818:Animals; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D008024:Ligands; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009101:Multiple Myeloma / Q000150:complications / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor
D002352:Carrier Proteins; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human