Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis.
Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis.
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DOI：
10.1016/j.joca.2011.11.009
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发表时间：
2012-02
影响因子：
7
通讯作者：
Serra, R.
中科院分区：
文献类型：
--
作者：
Chang, C. -F;Ramaswamy, G.;Serra, R.
初级纤毛几乎存在于包括软骨细胞在内的所有细胞类型中。研究表明，初级纤毛缺陷导致骨骼发育不良。本研究的目的是了解初级纤毛的丧失如何影响关节软骨。Ift88编码一种鞭毛内运输和初级纤毛形成所必需的蛋白质。在本研究中，我们使用Col2aCre；软骨细胞中原纤毛缺失的Ift88fl/fl转基因小鼠。Col2aCre;Ift88fl/fl关节软骨采用组织学染色、实时RT-PCR和微压痕进行表征。通过Ptch1和Gli1 mRNA的表达来检测Hedgehog （Hh）信号。western blot检测Gli3蛋白表达水平。Col2aCre;Ift88fl/fl关节软骨变厚，细胞密度增加，可能是由于软骨重塑过程中细胞凋亡减少。突变的关节软骨也显示骨关节炎（OA）标志物的表达增加，包括Mmp13、Adamts5、ColX和Runx2。通过微压痕测量，突变软骨的刚度降低也明显表明OA。通过Ptch1和Gli1的表达，发现突变型关节软骨中存在与OA相关的Hh信号上调。Col2aCre;Ift88fl/fl软骨也显示Gli3抑制因子与激活因子的比例降低。我们的研究结果表明，初级纤毛是关节软骨正常发育和维持所必需的。研究表明，初级纤毛是将全长Gli3加工成截断阻遏物形式所必需的。我们认为Col2aCre的OA症状；Ift88fl/fl软骨是由于Gli3减少Hh信号抑制所致。
Primary cilia are present in almost every cell type including chondrocytes. Studies have shown that defects in primary cilia result in skeletal dysplasia. The purpose of this study was to understand how loss of primary cilia affects articular cartilage. Ift88 encodes a protein that is required for intraflagellar transport and formation of primary cilia. In this study, we used Col2aCre;Ift88fl/fl transgenic mice in which primary cilia were deleted in chondrocytes. Col2aCre;Ift88fl/fl articular cartilage was characterized by histological staining, real time RT-PCR, and microindentation. Hedgehog (Hh) signaling was measured by expression of Ptch1 and Gli1 mRNA. The levels of Gli3 proteins were determined by western blot. Col2aCre;Ift88fl/fl articular cartilage was thicker and had increased cell density, likely due to decreased apoptosis during cartilage remodeling. Mutant articular cartilage also showed increased expression of osteoarthritis (OA) markers including Mmp13, Adamts5, ColX, and Runx2. OA was also evident by reduced stiffness in mutant cartilage as measured by microindentation. Up-regulation of Hh signaling, which has been associated with OA, was present in mutant articular cartilage as measured by expression of Ptch1 and Gli1. Col2aCre;Ift88fl/fl cartilage also demonstrated reduced Gli3 repressor to activator ratio. Our results indicate that primary cilia are required for normal development and maintenance of articular cartilage. It was shown that primary cilia are required for processing full length Gli3 to the truncated repressor form. We propose that OA symptoms in Col2aCre;Ift88fl/fl cartilage are due to reduced Hh signal repression by Gli3.
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影响因子：
2.8
作者：
Kaushik, Anjan P.;Martin, James A.;Zhang, Qihong;Sheffield, Val C.;Morcuende, Jose A.
通讯作者：
Morcuende, Jose A.
影响因子：
30.8
作者：
HUI, CC;JOYNER, AL
通讯作者：
JOYNER, AL
影响因子：
4.6
作者：
Hu, MC;Mo, R;Rosenblum, ND
通讯作者：
Rosenblum, ND
影响因子：
4.6
作者：
Hilton, MJ;Tu, XL;Long, FX
通讯作者：
Long, FX
影响因子：
4.9
作者：
Dreier R
通讯作者：
Dreier R