title: Col10a1-Runx2 transgenic mice with delayed chondrocyte maturation are less susceptible to developing osteoarthritis.
abstract: Osteoarthritis (OA) is the most common joint disease affecting close to 27 million Americans. The pathological change of OA joint is characterized by cartilage degradation and osteophyte formation that have been associated with OA initiation and progression respectively. Upon OA progression, articular chondrocytes undergo hypertrophic differentiation, a process usually occurs only in growth plate chondrocytes during endochondral ossification, suggesting a role of chondrocyte hypertrophy in OA pathogenesis. However, how altered chondrocyte hypertrophy, i.e. accelerated or delayed chondrocyte hypertrophy, influences OA development has not been fully elucidated. We have previously generated transgenic (TG) mice over-expressing Runx2, an essential transcription factor for chondrocyte hypertrophy, using hypertrophic chondrocyte-specific mouse type X collagen gene (Col10a1) control elements. These Col10a1-Runx2 TG mice show delayed chondrocyte hypertrophy and apoptosis in long bone sections of embryonic and new-born mice compared to their wild-type (WT) littermates. Here, we report further analysis of the skeletal phenotypes of these mice at postnatal stages. We have performed histological analysis of 1-month old TG and WT mice. Delayed chondrocyte hypertrophy was also observed in growth plate of TG mice. In addition, μCT analysis showed that the femur length was significantly shorter in TG mice (p = 0.033). Thinner cortical bone and markedly decreased BV/TV were also detected in TG mice compared to their WT littermates (p = 0.027), suggesting that delayed chondrocyte hypertrophy affects postnatal long bone development. Interestingly, histological analysis detected less articular cartilage absorption, while immunohistochemistry assay detected upregulated Sox9 expression in TG mouse joints compared to WT controls, implying that delayed chondrocyte hypertrophy may be OA protective. Indeed, we have performed Tgf-β1 injection and enforced uphill treadmill running (TTR model) to induce OA in TG and WT littermates. The results showed that WT littermates displayed characteristic pathology of fibrotic remodeling at the joint margins and focal cartilage erosion, while the joints in TG mice were essentially protected from remodeling responses, demonstrating that mice with delayed chondrocyte hypertrophy are not susceptible to developing OA. Further translational studies characterizing the role of chondrocyte hypertrophy during OA progression will facilitate identification of therapeutic targets to stop or slow down this degenerative and progressive human joint disease.
authors: Department of Hematology and Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, China ; Department of Anatomy and Cell Biology, Rush University Medical Center Chicago, IL 60612, USA.
authors: Yaojuan
authors: Y
authors: Lu
authors: Department of Anatomy and Cell Biology, Rush University Medical Center Chicago, IL 60612, USA.
authors: Ming
authors: M
authors: Ding
authors: Department of Hematology and Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, China.
authors: Na
authors: N
authors: Li
authors: Department of Hematology and Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, China.
authors: Qian
authors: Q
authors: Wang
authors: Department of Internal Medicine (Rheumatology), Rush University Medical Center Chicago, IL 60612, USA.
authors: Jun
authors: J
authors: Li
authors: Department of Biochemistry, Rush University Medical Center Chicago, IL 60612, USA.
authors: Xin
authors: X
authors: Li
authors: Department of Hematology and Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, China.
authors: Junxia
authors: J
authors: Gu
authors: Department of Biochemistry, Rush University Medical Center Chicago, IL 60612, USA.
authors: Hee-Jeong
authors: HJ
authors: Im
authors: Department of Orthopaedic Surgery, Xiangya Hospital, Central South University Changsha 410008, China.
authors: Guanghua
authors: G
authors: Lei
authors: Department of Hematology and Hematological Laboratory Science, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University Zhenjiang 212013, China ; Department of Anatomy and Cell Biology, Rush University Medical Center Chicago, IL 60612, USA.
authors: Qiping
authors: Q
authors: Zheng
keywords: Col10a1; Runx2; Tgf-β1 injection; chondrocyte hypertrophy or maturation; osteoarthritis; transgenic mice; treadmill running
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