Establishment of treatment systematization aimed at inhibition of mandibular condyle resorption in osteoarthritis

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以下研究：2003年和2004年，我们检测了低分子量透明质酸（HA）对培养的关节软骨细胞的影响，并探讨了HA片段化的调控方法。在这项研究中，我们阐明了HA的降解或断裂加速了软骨降解，并上调了关节中的基质金属蛋白酶（Ohno-Nakahara M.等，135：567-575，2004 ; Ohno S.等，Arthritis Rheum. 52：800-809，2005）。此外，我们阐明了在高分子量HA的产生中起关键作用的HAS 2基因表达通过在培养的滑膜细胞上作用生长因子如TGF-β而大大促进（Tanimoto K.例如，J Dent.Res.，八十三：40-44，2005）。在2005年，我们检测了高强度拉伸负荷对培养的软骨细胞和滑膜细胞中HA代谢的影响。本研究阐明了高强度周期性拉伸负荷可增强滑膜细胞HYAL 2基因表达和HA酶活性。虽然HYAL 2基因在培养的软骨细胞表达也增强拉伸负荷，HAase活性没有改变。此外，我们还发现HYAL 2 siRNA抑制了高强度拉伸载荷下滑膜细胞HA酶活性，提示HA断裂直接参与了软骨降解，而高强度拉伸载荷诱导的HA表达是导致HA断裂的生化原因。另一方面，因此TGF-β诱导高分子量HA的产生，强烈表明TGF-β是软骨降解随后HA断裂的有效抑制剂。

To elucidate the mechanism of cartilage degradation and pathologic progress in osteoarthritis (OA), we carried out sequential studies as follows by means of biochemical methods.In 2003 and 2004, we examined the effects of low molecular weight hyaluronan (HA) on cultured articular chondrocytes and pursued the regulatory method for HA fragmentation. In this study, we clarified that degradation or fragmentation of HA accelerates cartilage degradation with up-regulation of matrix metalloproteinases in articular joints (Ohno-Nakahara M. et al., J.Biochem. 135 : 567-575, 2004 ; Ohno S. et al., Arthritis Rheum. 52 : 800-809, 2005). In addition, we clarified that HAS2, which played a crucial role in production of high molecular weight HA, gene expression was greatly facilitated by acting growth factor such as TGF-β on cultured synovial membrane cells (Tanimoto K. et al., J Dent.Res., 83 : 40-44, 2005).In 2005, we examined the effects of high magnitude tensile load on HA metabolism in cultured chondrocytes and synovial membrane cells. In this study, we clarified HYAL2 gene expression and HAase activity in cultured synovial membrane cells were enhanced by high magnitude cyclic tensile load. Although HYAL2 gene expression in cultured chondrocytes was also enhanced by tensile load, HAase activity was not changed. In addition, we clarified that HYAL2 siRNA inhibited HAase activity of synovial membrane cells subjected high magnitude tensile load.These results suggested that HA fragmentation was directly involved in cartilage degradation and the biochemical cause for HA fragmentation was HYAL2 expression induced by high magnitude tensile load. On the other hand, therefore TGF-β induced production of high molecular weight HA, it was strongly suggested that TGF-β was an effective inhibitor of cartilage degradation followed by HA fragmentation.