Rheumatology Advance Access published online on September 17, 2009
Rheumatology, doi:10.1093/rheumatology/kep300
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Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis
1Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Montreal, Quebec and 2Duval Orthopaedic Clinic, Laval, Quebec, Canada.
Correspondence to:
Johanne Martel-Pelletier, Osteoarthritis Research Unit, University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. E-mail: jm{at}martelpelletier.ca
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Abstract |
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Objectives. Earlier studies suggest the involvement of osteoprotegerin (OPG), RANK and RANK ligand (RANKL) in OA subchondral bone metabolism; however, few studies have looked at their functional consequences on chondrocytes. We compared the expression/production of OPG, RANK and RANKL on human normal and OA chondrocytes, and evaluated, on OA chondrocytes, their modulation by some catabolic factors. Furthermore, the role of OPG and RANKL on the production of catabolic/anabolic factors was assessed.
Methods. Expression was determined using real-time PCR, production of RANK and RANKL by flow cytometry and that of OPG by ELISA. Modulation of these factors was determined upon treatment with IL-1β, TNF-
and PGE2. The functional consequences were examined following treatment with soluble RANKL or OPG-Fc (OPG without the heparin-binding domain).
Results. OPG, RANK and RANKL were expressed and produced by human chondrocytes. Membranous RANK was produced only by an OA chondrocyte subpopulation (29%) localized throughout the cartilage. The OPG/RANKL ratio was significantly (P = 0.05) reduced on the OA chondrocytes, whereas the RANK/RANKL ratio was significantly (P < 0.03) increased. OPG and membranous RANKL levels were significantly enhanced by IL-1β, TNF- and PGE2, whereas membranous RANK was significantly increased only with IL-1β. Administration of soluble RANKL had no effect on the OA chondrocytes. However, addition of OPG-Fc significantly stimulated MMP-13 (P = 0.05) and protease-activated receptor-2 (PAR-2) (P < 0.04) production.
Conclusions. Our findings showed that human chondrocytes express and produce OPG, RANK and RANKL. OA chondrocyte treatment with catabolic factors pointed towards an increased biological effect of OPG. Interestingly, OPG appears to be involved in OA progression by increasing two catabolic factors involved in cartilage pathophysiology.
KEY WORDS: Osteoarthritis, Chondrocytes, OPG, RANK, RANKL
Submitted 17 March 2009;
revised version accepted 13 August 2009.
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