权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Biochemical elucidation of mandibular condyle cartilage destruction mechanism

下颌髁突软骨破坏机制的生化阐明

基本信息

批准号：
11557166
负责人：
TANNE Kazuo
金额：
$ 4.29万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557166/
关键词：
hyaluronic acid cytokine hyaluronic acid synthases (HASs)osteoarthritis articular cartilage synovial membrane low molecular weight mechanical loading 軟骨基質 MMP TIMP

项目摘要

In order to elucidate the mechanism of cartilage degradation and pathologic progress in osteoarthritis (OA), we carried out series of studies by means of biochemical methods.In 1999, we examined the matrix metabolism and the gene expression of MMP and TIMP in cultured rabbit articular chondrocytes subjected to high magnitude tensile load to clarify the effects of mechanical stress on cartilage degradation. In this study, we clarified that high magnitude tensile load changed cell shape and decreased the production of cartilage matrix molecules such as hyaluronic acid, proteoglycan and type II collagen. In addition, we demonstrated that high magnitude tensile load increased expression of MMP-1, -3, -9 and IL-1β, TNF-α, which were involved in cartilage matrix loss.In conclusion, we revealed in this study that high magnitude tensile load caused the degradation of cartilage directly by reducing the production of matrix molecules and enhancing the expression of catabolic factors.In 2000, we investigated the expression patterns of hyaluronic acid synthetases (HASs), which regulate the molecular weight of hyaluronic acid, and clarified the mechanism of accumulation of low molecular hyaluronic acid in synovial fluid of patients with OA.In this study, we demonstrated that HAS2, which synthesizes the high molecular weight hyaluronic acid, was predominantly expressed in normal synovial membrane and cartilage, whereas HAS3, which synthesizes the low molecular weight hyaluronic acid, was induced highly by proinflammatory cytokaines such as IL-1β and TNF-α.These results suggest that the low molecular weight hyaluronic acid is produced during synthesis by HAS3 induced by cytokines under inflammatory conditions and this low molecular weight HA may cause the reduction of the visco-elasity of synovial fluid, and enhance the inflammatory response.

为了阐明骨关节炎（OA）软骨降解和病理过程的机制，我们采用生物化学方法进行了一系列研究，1999年，我们检测了机械应力对体外培养的兔关节软骨细胞基质代谢和MMP、TIMP基因表达的影响，以阐明机械应力对软骨降解的影响。在这项研究中，我们阐明了高强度的拉伸负荷改变了细胞的形状，减少了软骨基质分子，如透明质酸，蛋白多糖和II型胶原蛋白的产生。另外，我们发现高强度的拉伸负荷增加了MMP-1、MMP-3、MMP-9和IL-1β、TNF-α的表达，这些都参与了软骨基质的丢失。总之，我们在这项研究中揭示了高强度的拉伸负荷通过减少基质分子的产生和增加分解代谢因子的表达直接导致软骨的降解。我们研究了调节透明质酸分子量的透明质酸合成酶（HASs）的表达模式，并阐明了OA患者滑液中低分子透明质酸积累的机制。在这项研究中，我们证明了合成高分子量透明质酸的HAS 2，主要在正常滑膜和软骨中表达，而合成低分子量透明质酸的HAS 3，IL-1β和TNF-α等促炎因子可高度诱导α。这些结果表明，低分子量透明质酸是在炎症条件下由细胞因子诱导的HAS 3合成过程中产生的，并且这低分子量HA可引起关节液粘弹性降低，增强炎症反应。