在小鼠模型中，过氧化物酶体增殖物激活受体γ软骨特异性缺失与软骨内骨化异常及软骨生长发育受损的关联。
Association of cartilage-specific deletion of peroxisome proliferator-activated receptor γ with abnormal endochondral ossification and impaired cartilage growth and development in a murine model.
作者信息
Monemdjou Roxana, Vasheghani Faezeh, Fahmi Hassan, Perez Gemma, Blati Meryem, Taniguchi Noboru, Lotz Martin, St-Arnaud René, Pelletier Jean-Pierre, Martel-Pelletier Johanne, Beier Frank, Kapoor Mohit
机构信息
University of Montreal Hospital Research Centre and University of Montreal, Montreal, Quebec, Canada.
出版信息
Arthritis Rheum. 2012 May;64(5):1551-61. doi: 10.1002/art.33490.
OBJECTIVE
Long bones develop through the strictly regulated process of endochondral ossification within the growth plate, resulting in the replacement of cartilage by bone. Defects in this process can result in skeletal abnormalities and a predisposition to degenerative joint diseases such as osteoarthritis (OA). Studies suggest that activation of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is an important therapeutic target in OA. To devise PPARγ-related therapies in OA, it is critical to identify the role of this transcription factor in cartilage biology. Therefore, this study sought to determine the in vivo role of PPARγ in endochondral ossification and cartilage development, using cartilage-specific PPARγ-knockout (KO) mice.
METHODS
Cartilage-specific PPARγ-KO mice were generated using the Cre/loxP system. Histomorphometric and immunohistochemical analyses were performed to assess the patterns of ossification, proliferation, differentiation, and hypertrophy of chondrocytes, skeletal organization, bone density, and calcium deposition in the KO mice.
RESULTS
PPARγ-KO mice exhibited reductions in body length, body weight, length of the long bones, skeletal growth, cellularity, bone density, calcium deposition, and trabecular bone thickness, abnormal organization of the growth plate, loss of columnar organization, shorter hypertrophic zones, and delayed primary and secondary ossification. Immunohistochemical analyses for Sox9, 5-bromo-2'-deoxyuridine, p57, type X collagen, and platelet endothelial cell adhesion molecule 1 revealed reductions in the differentiation, proliferation, and hypertrophy of chondrocytes and in vascularization of the growth plate in mutant mice. Isolated chondrocytes and cartilage explants from mutant mice showed aberrant expression of Sox9 and extracellular matrix markers, including aggrecan, type II collagen, and matrix metalloproteinase 13. In addition, chondrocytes from mutant mice exhibited enhanced phosphorylation of p38 and decreased expression of Indian hedgehog.
CONCLUSION
The presence of PPARγ is required for normal endochondral ossification and cartilage development in vivo.
目的
长骨通过生长板内严格调控的软骨内成骨过程发育，导致软骨被骨替代。该过程中的缺陷可导致骨骼异常，并易患骨关节炎（OA）等退行性关节疾病。研究表明，转录因子过氧化物酶体增殖物激活受体γ（PPARγ）的激活是OA的一个重要治疗靶点。为了设计OA中与PPARγ相关的疗法，确定该转录因子在软骨生物学中的作用至关重要。因此，本研究试图利用软骨特异性PPARγ基因敲除（KO）小鼠来确定PPARγ在软骨内成骨和软骨发育中的体内作用。
方法
使用Cre/loxP系统构建软骨特异性PPARγ-KO小鼠。进行组织形态计量学和免疫组织化学分析，以评估KO小鼠中软骨细胞的骨化、增殖、分化和肥大模式、骨骼结构、骨密度和钙沉积情况。
结果
PPARγ-KO小鼠的体长、体重、长骨长度、骨骼生长、细胞数量、骨密度、钙沉积和小梁骨厚度均降低，生长板结构异常，柱状结构丧失，肥大区缩短，初级和次级骨化延迟。对Sox9、5-溴-2'-脱氧尿苷、p57、X型胶原和血小板内皮细胞黏附分子1的免疫组织化学分析显示，突变小鼠软骨细胞的分化、增殖和肥大以及生长板血管化均减少。来自突变小鼠的分离软骨细胞和软骨外植体显示Sox9和细胞外基质标志物（包括聚集蛋白聚糖、II型胶原和基质金属蛋白酶13）的表达异常。此外，来自突变小鼠的软骨细胞p38磷酸化增强，印度刺猬蛋白表达降低。
结论
体内正常的软骨内成骨和软骨发育需要PPARγ的存在。
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