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

为了阐明骨关节炎（OA）软骨退化的机制和病理进展，我们通过生化方法进行了如下顺序的研究。2003年和2004年，我们研究了低分子量透明质酸（HA）对培养关节软骨细胞的影响，并探索了HA破碎的调控方法。在这项研究中，我们阐明了透明质酸的降解或破碎通过上调关节中基质金属蛋白酶加速软骨降解（Ohno-Nakahara M. etal .， J.Biochem.）。[j]; 2004；黄志强，王志强，等。中华风湿病杂志。32(2):398 - 398,2005。此外，我们澄清了在高分子量HA的产生中起关键作用的HAS2，在培养的滑膜细胞上，TGF-β等生长因子极大地促进了基因的表达（Tanimoto K. et al., J dentet . res .）。农业学报，83:40-44,2005)。2005年，我们研究了高强度拉伸负荷对培养软骨细胞和滑膜细胞HA代谢的影响。在本研究中，我们明确了在培养的滑膜细胞中，高强度循环拉伸载荷增强了HYAL2基因表达和HAase活性。虽然拉伸载荷也增强了培养软骨细胞中HYAL2基因的表达，但HAase活性没有改变。此外，我们澄清了HYAL2 siRNA抑制滑膜细胞在高强度拉伸负荷下的HAase活性。这些结果表明，HA碎裂直接参与软骨降解，而HA碎裂的生化原因是高强度拉伸载荷诱导的HYAL2表达。另一方面，因此TGF-β诱导高分子量HA的产生，这强烈表明TGF-β是软骨降解和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.