Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability
Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability
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DOI：
10.1002/art.22041
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发表时间：
2006-08-01
影响因子：
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通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
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作者：
Kamekura, Satoru;Kawasaki, Yosuke;Kawaguchi, Hiroshi
目标。通过在小鼠膝关节中产生不稳定性，我们试图确定矮小相关转录因子2 （RUNX-2）的参与，这是软骨细胞肥大所必需的，在骨关节炎（OA）的发展。通过手术切除runx -2（+/-）杂合型runx -2缺陷小鼠（runx -2(+/-)）的内侧副韧带和切除膝关节内侧半月板，建立实验性小鼠OA模型。通过组织学和影像学分析比较胫骨内侧软骨的软骨破坏和骨赘形成。免疫组化检测X型胶原和基质金属蛋白酶13 （MMP-13）的定位。在Runx2缺失位点（Runx2(+/lacZ)）插入lacZ基因的杂合子RUNX-2缺陷小鼠（Runx2(+/lacZ)）中，通过X-Gal染色确定RUNX-2的定位。实时逆转录-聚合酶链式反应分析检测X型胶原蛋白、MMP-13和RUNX-2的信使RNA水平。在OA早期野生型小鼠关节软骨中，RUNX-2几乎与X型胶原同时表达，但早于MMP-13。Runx2（+/-）和Runx2（+/lacZ）小鼠骨骼发育正常，关节软骨发育正常；然而，在诱导膝关节不稳定后，与野生型小鼠相比，它们表现出软骨破坏和骨赘形成减少，X型胶原蛋白和MMP-13表达减少。在诱导关节不稳定后，RUNX-2通过软骨细胞肥大和基质破坏参与OA的发病机制。
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.Conclusion. RUNX-2 contributes to the pathogenesis of OA through chondrocyte hypertrophy and matrix breakdown after the induction of joint instability.