Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis.
OBJECTIVE
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-1beta, TNF-alpha and PGE(2). 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-1beta, TNF-alpha and PGE(2), whereas membranous RANK was significantly increased only with IL-1beta. 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.
Kwan Tat
Steeve
S
Osteoarthritis Research Unit, University of Montreal Hospital Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada.
Amiable
Nathalie
N
Pelletier
Jean-Pierre
JP
Boileau
Christelle
C
Lajeunesse
Daniel
D
Duval
Nicolas
N
Martel-Pelletier
Johanne
J
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D053244:Osteoprotegerin / Q000096:biosynthesis* / Q000502:physiology; D016133:Polymerase Chain Reaction / Q000379:methods; D053245:RANK Ligand / Q000096:biosynthesis / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D053583:Interleukin-1beta; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone