Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability.
OBJECTIVE
By producing instability in mouse knee joints, we attempted to determine the involvement of runt-related transcription factor 2 (RUNX-2), which is required for chondrocyte hypertrophy, in the development of osteoarthritis (OA).


METHODS
An experimental mouse OA model was created by surgical transection of the medial collateral ligament and resection of the medial meniscus of the knee joints of heterozygous RUNX-2-deficient (Runx2+/-) mice and wild-type littermates. Cartilage destruction and osteophyte formation in the medial tibial cartilage were compared by histologic and radiographic analyses. Localization of type X collagen and matrix metalloproteinase 13 (MMP-13) was examined by immunohistochemistry. Localization of RUNX-2 was determined by X-Gal staining in heterozygous RUNX-2-deficient mice with the lacZ gene insertion at the Runx2-deletion site (Runx2+/lacZ). Messenger RNA levels of type X collagen, MMP-13, and RUNX-2 were examined by real-time reverse transcriptase-polymerase chain reaction analysis.


RESULTS
RUNX-2 was induced in the articular cartilage of wild-type mice at the early stage of OA, almost simultaneously with type X collagen but earlier than MMP-13. Runx2+/- and Runx2+/lacZ mice showed normal skeletal development and articular cartilage; however, after induction of knee joint instability, they exhibited decreased cartilage destruction and osteophyte formation, along with reduced type X collagen and MMP-13 expression, as compared with wild-type mice.


CONCLUSIONS
RUNX-2 contributes to the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability.
Kamekura
Satoru
S
Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Kawasaki
Yosuke
Y
Hoshi
Kazuto
K
Shimoaka
Takashi
T
Chikuda
Hirotaka
H
Maruyama
Zenjiro
Z
Komori
Toshihisa
T
Sato
Shingo
S
Takeda
Shu
S
Karsenty
Gerard
G
Nakamura
Kozo
K
Chung
Ung-il
UI
Kawaguchi
Hiroshi
H
D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017353:Gene Deletion; D007593:Joint Instability / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D053509:Matrix Metalloproteinase 13; D017888:Medial Collateral Ligament, Knee / Q000293:injuries / Q000601:surgery; D008592:Menisci, Tibial / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013264:Stifle / Q000293:injuries / Q000473:pathology / Q000601:surgery; D000070600:Tibial Meniscus Injuries
D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; C493716:Runx2 protein, mouse; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse