Prevention of cartilage destruction with intraarticular osteoclastogenesis inhibitory factor/osteoprotegerin in a murine model of osteoarthritis.
OBJECTIVE
To investigate the effect of osteoclastogenesis inhibitory factor/osteoprotegerin (OPG) on chondrocytes in the development of osteoarthritis (OA) in vivo.


METHODS
To determine the role of endogenous OPG in the progression of OA, OA was surgically induced in OPG+/- mice and their wild-type (WT) littermates. To determine the role of exogenous OPG, knee joints of C57BL/6J mice with surgically induced OA were injected intraarticularly with recombinant human OPG (rHuOPG) or vehicle 5 times a week. All mice were euthanized 4 weeks after OA induction; joints were harvested and evaluated immunohistochemically.


RESULTS
Although OA changes were induced in both WT and OPG+/- mice, the degenerative changes in the articular cartilage were significantly enhanced in OPG+/- mice. In C57BL/6J mice with surgically induced OA, intraarticular OPG administration protected the articular cartilage from the progression of OA. The Mankin and cartilage destruction scores in OPG-treated animals were approximately 50% of those seen in the control group. Furthermore, OPG administration significantly protected articular cartilage thickness. Findings of the TUNEL assay indicated that rHuOPG prevented chondrocyte apoptosis in joints with surgically induced OA. Results of immunostaining indicated that OPG protein was detected in the synovium and in resident chondrocytes at higher levels in the OPG-treated group than in the control group.


CONCLUSIONS
These data indicate that endogenous OPG had a protective effect against the cartilage destruction that occurs during OA progression. Furthermore, direct administration of rHuOPG to articular chondrocytes prevented cartilage destruction in an experimental murine model of OA via prevention of chondrocyte apoptosis.
Shimizu
Sadanori
S
Tokyo Medical and Dental University, Tokyo, Japan.
Asou
Yoshinori
Y
Itoh
Soichiro
S
Chung
Ung-il
UI
Kawaguchi
Hiroshi
H
Shinomiya
Kenichi
K
Muneta
Takeshi
T
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects*; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007270:Injections, Intra-Articular; D051379:Mice; D008810:Mice, Inbred C57BL; D020370:Osteoarthritis, Knee / Q000188:drug therapy / Q000378:metabolism*; D053244:Osteoprotegerin / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D053244:Osteoprotegerin