New perspective in osteoarthritis: the OPG and RANKL system as a potential therapeutic target?
Bone remodelling is tightly regulated by a molecular triad composed of OPG/RANK/RANKL. The receptor activator of NF-kappaB ligand (RANKL) (localized on osteoblasts) enhances osteoclastogenesis via interaction with its receptor RANK (localized on osteoclasts), whereas osteoprotegerin (OPG) (produced by osteoblasts) inhibits this osteoclastogenesis by binding to RANKL. The equilibrium between OPG and RANKL plays a crucial role in the pathophysiology of bone. Although some studies have shown the efficacy of OPG as a therapeutic agent against bone resorption, its bioavailability and mechanism of action after binding to RANKL have only recently been studied. A mechanistic investigation based on what becomes of OPG after binding to cells expressing membranous RANKL demonstrated an internalization process of OPG through the clathrin pathway prior to proteasomal and/or lysosomal degradation. Interestingly, the OPG internalization process reduced the half-life of RANKL. Recent evidence has shown that subchondral bone alterations in osteoarthritis (OA) are intimately involved in cartilage degradation, and that OPG/RANKL may be implicated. Data show that human OA subchondral bone osteoblasts have abnormal OPG and RANKL levels and consequently an altered OPG and RANKL ratio. Further data also reveal the involvement of some osteotropic factors in these altered levels and that some of these factors generally target RANKL with a differential modulation of the RANKL isoforms. Altogether, data suggest that this system could be targeted as a new strategy for the treatment of OA.
Tat
Steeve Kwan
SK
Osteoarthritis Research Unit, University of Montreal Hospital Centre, Notre-Dame Hospital, Montreal, Quebec, Canada.
Pelletier
Jean-Pierre
JP
Velasco
Carmen Ruiz
CR
Padrines
Marc
M
Martel-Pelletier
Johanne
J
D000818:Animals; D006801:Humans; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D013379:Substrate Specificity
D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B