Moulharat N, Lesur C, Thomas M, Rolland-Valognes G, Pastoureau P, Anract P, De Ceuninck F, Sabatini M
Division of Rheumatology, Institut de Recherches Servier, Suresnes, France.
Osteoarthritis Cartilage. 2004 Apr;12(4):296-305. doi: 10.1016/j.joca.2003.11.009.
Aggrecan is degraded by Aggrecanases (ADAMTS-4 and -5) and MMPs, which cleave its core protein at different sites. Transforming growth factor (TGF)beta is known to stimulate matrix formation in cartilage, and ADAMTS-4 production in synoviocytes. The aim of this in-vitro study was to examine the effects of TGFbeta on aggrecanase production in human cartilage.
Expression of ADAMTS-4 and -5 in chondrocyte cultures from normal or osteoarthritic cartilage was studied at mRNA level by RT-PCR. Aggrecanase activity was examined by western blot of aggrecanase-generated neoepitope NITEGE, and by measure of proteoglycan degradation in cartilage explants.
TGFbeta strongly increased mRNA levels of ADAMTS-4, while ADAMTS-5 was expressed in a constitutive way in chondrocytes from normal and osteoathritic cartilage. TGFbeta also increased NITEGE levels and proteoglycan degradation. Addition of an aggrecanase inhibitor blocked the increase of NITEGE, and partially inhibited proteoglycan degradation.
TGFbeta stimulates ADAMTS-4 expression and aggrecan degradation in cartilage. This catabolic action seems to be partially mediated by aggrecanases. It is, therefore, proposed that the role of TGFbeta in cartilage matrix turnover is not limited to anabolic and anti-catabolic actions, but also extends to selective degradation of matrix components such as aggrecan.
聚集蛋白聚糖可被聚集蛋白聚糖酶（ADAMTS - 4和 - 5）及基质金属蛋白酶降解，这些酶在不同位点切割其核心蛋白。已知转化生长因子（TGF）β可刺激软骨中的基质形成以及滑膜细胞中ADAMTS - 4的产生。本体外研究的目的是检测TGFβ对人软骨中聚集蛋白聚糖酶产生的影响。
通过逆转录聚合酶链反应（RT - PCR）在mRNA水平研究正常或骨关节炎软骨的软骨细胞培养物中ADAMTS - 4和 - 5的表达。通过对聚集蛋白聚糖酶产生的新表位NITEGE进行蛋白质印迹分析以及测量软骨外植体中蛋白聚糖的降解来检测聚集蛋白聚糖酶活性。
TGFβ显著增加ADAMTS - 4的mRNA水平，而ADAMTS - 5在正常和骨关节炎软骨的软骨细胞中以组成性方式表达。TGFβ还增加了NITEGE水平和蛋白聚糖降解。添加聚集蛋白聚糖酶抑制剂可阻断NITEGE的增加，并部分抑制蛋白聚糖降解。
TGFβ刺激软骨中ADAMTS - 4的表达和聚集蛋白聚糖的降解。这种分解代谢作用似乎部分由聚集蛋白聚糖酶介导。因此，有人提出TGFβ在软骨基质周转中的作用不仅限于合成代谢和抗分解代谢作用，还扩展到对诸如聚集蛋白聚糖等基质成分的选择性降解。
