title: New insights in myeloma-induced osteolysis.
abstract: Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow (BM) and characterized by a high capacity for bone destruction. Almost all patients with MM have early osteolytic lesions, which result mainly from increased bone resorption related to stimulation of osteoclast recruitment and activity in the immediate vicinity of myeloma cells. The recent discovery of Osteoprotegerin (OPG) and the subsequent identification of its ligand RANKL have provided new insights in the regulation of osteoclastogenesis. The ratio OPG/RANKL is critical for the regulation of bone remodeling maintaining the balance between osteoblastic and osteoclastic activity. This review summarizes the new concept that myeloma cells induce in bone environment an imbalance in the OPG/RANKL system responsible for osteolysis observed in patients. Indeed, myeloma cells increase in bone environment the expression of the potent osteoclastogenic factor RANKL and decrease the osteoprotective factor OPG production. Biological mechanisms involved in these processes are discussed. Furthermore, the chemokines MIP-1alpha and MIP-1beta belonging to the RANTES family are potent osteoclastogenic factors produced by myeloma cells and participate in myeloma-associated bone disease. These data open new avenues for the treatment of bone disease in MM and highlight the promising therapeutical interest of RANKL inhibitors (OPG and RANK-Fc) and MIP-1 inhibitors in the management of myeloma-associated osteolysis, besides bisphosphonates.
authors.affiliation: INSERM U463, 9 quai Moncousu 44 093 Nantes cedex I France. sbarille@nantes.inserm.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Barillé-Nion
authors.forename: Régis
authors.initials: R
authors.lastname: Bataille
mesh_terms: D000818:Animals; D016723:Bone Remodeling; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004164:Diphosphonates / Q000627:therapeutic use; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy / Q000209:etiology; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D009101:Multiple Myeloma / Q000150:complications*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use
chemical_list: D002352:Carrier Proteins; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004164:Diphosphonates; D006023:Glycoproteins; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse