Primary cilia disassembly down-regulates mechanosensitive hedgehog signalling: a feedback mechanism controlling ADAMTS-5 expression in chondrocytes.
Primary cilia disassembly down-regulates mechanosensitive hedgehog signalling: a feedback mechanism controlling ADAMTS-5 expression in chondrocytes.
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DOI：
10.1016/j.joca.2013.12.016
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发表时间：
2014-03
影响因子：
7
通讯作者：
Knight MM
中科院分区：
文献类型：
--
作者：
Thompson CL;Chapple JP;Knight MM
刺猬信号是由初级纤毛介导的，并促进骨关节炎的软骨变性。原发性纤毛受到病理刺激的影响，在骨关节炎软骨中纤毛的长度和患病率增加。本研究旨在探讨关节软骨细胞中机械负荷、hedgehog信号传导和纤毛脱落之间的关系。原代牛关节软骨细胞受到循环拉伸应变（CTS; 0.33 Hz， 10%或20%应变）。real-time PCR检测Hedgehog通路激活（Ptch1, Gli1）和A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 （ADAMTS-5）的表达。从Tg737ORPK小鼠中产生的软骨细胞系被用来研究纤毛在这种反应中的作用。用免疫细胞化学和共聚焦显微镜测定纤毛的长度和发病率。机械应变上调印度刺猬表达并激活刺猬信号传导。Ptch1、Gli1和ADAMTS-5的表达在10% CTS后升高，20% CTS后不升高。通路激活需要初级纤毛的功能，而在缺乏纤毛的Tg737ORPK细胞中未观察到。机械载荷显著减小纤毛长度，随着应变大小的增加，纤毛逐渐变短。抑制组蛋白去乙酰化酶6 (HDAC6)，一种微管蛋白去乙酰化酶，阻止纤毛分解，恢复机械敏感的刺猬信号传导和ADAMTS-5在20% CTS下的表达。这项研究首次证明，机械负荷激活了成人关节软骨细胞中原发性纤毛介导的刺猬信号传导和ADAMTS-5的表达，但由于hdac6介导的纤毛断裂，这种反应在高负荷时丢失。该研究为初级纤毛和关节软骨机械负荷的作用提供了新的机制见解。
Hedgehog signalling is mediated by the primary cilium and promotes cartilage degeneration in osteoarthritis. Primary cilia are influenced by pathological stimuli and cilia length and prevalence are increased in osteoarthritic cartilage. This study aims to investigate the relationship between mechanical loading, hedgehog signalling and cilia disassembly in articular chondrocytes. Primary bovine articular chondrocytes were subjected to cyclic tensile strain (CTS; 0.33 Hz, 10% or 20% strain). Hedgehog pathway activation (Ptch1, Gli1) and A Disintegrin And Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS-5) expression were assessed by real-time PCR. A chondrocyte cell line generated from the Tg737ORPK mouse was used to investigate the role of the cilium in this response. Cilia length and prevalence were quantified by immunocytochemistry and confocal microscopy. Mechanical strain upregulates Indian hedgehog expression and activates hedgehog signalling. Ptch1, Gli1 and ADAMTS-5 expression were increased following 10% CTS, but not 20% CTS. Pathway activation requires a functioning primary cilium and is not observed in Tg737ORPK cells lacking cilia. Mechanical loading significantly reduced cilium length such that cilia became progressively shorter with increasing strain magnitude. Inhibition of histone deacetylase 6 (HDAC6), a tubulin deacetylase, prevented cilia disassembly and restored mechanosensitive hedgehog signalling and ADAMTS-5 expression at 20% CTS. This study demonstrates for the first time that mechanical loading activates primary cilia-mediated hedgehog signalling and ADAMTS-5 expression in adult articular chondrocytes, but that this response is lost at high strains due to HDAC6-mediated cilia disassembly. The study provides new mechanistic insight into the role of primary cilia and mechanical loading in articular cartilage.
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影响因子：
--
作者：
Phan, Mimi N.;Leddy, Holly A.;Votta, Bartholomew J.;Kumar, Sanjay;Levy, Dana S.;Lipshutz, David B.;Lee, Suk Hee;Liedtke, Wolfgang;Guilak, Farshid
通讯作者：
Guilak, Farshid
影响因子：
56.9
作者：
Rohatgi, Rajat;Milenkovic, Ljiljana;Scott, Matthew P.
通讯作者：
Scott, Matthew P.
DOI：
10.1007/978-1-60761-984-0_6
发表时间：
2011-01-01
期刊：
3D CELL CULTURE: METHODS AND PROTOCOLS
影响因子：
--
作者：
Lee, David A.;Brand, June;Chowdhury, Tina T.
通讯作者：
Chowdhury, Tina T.
影响因子：
7
作者：
Rich, D. R.;Clark, A. L.
通讯作者：
Clark, A. L.
影响因子：
7.8
作者：
Qin, Hongmin;Diener, Dennis R;Geimer, Stefan;Cole, Douglas G;Rosenbaum, Joel L
通讯作者：
Rosenbaum, Joel L