Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage.
Expression profiling of metalloproteinases and their inhibitors in synovium and cartilage.
复制标题
金属蛋白酶及其抑制剂在滑膜和软骨中的表达分析。
DOI：
10.1186/ar2013
复制
发表时间：
2006
影响因子：
4.9
通讯作者：
Clark, Ian M
中科院分区：
文献类型：
--
作者：
Davidson, Rose K;Waters, Jasmine G;Kevorkian, Lara;Darrah, Clare;Cooper, Adele;Donell, Simon T;Clark, Ian M
骨关节炎（OA）中的软骨破坏被认为是由两个主要的酶家族介导的;基质金属蛋白酶（MMP）负责软骨胶原分解，而来自“具有血小板反应蛋白基序的去整合素和金属蛋白酶结构域”（ADAMTS）家族的酶介导软骨聚集蛋白聚糖损失。金属蛋白酶组织抑制剂（TIMPs）调节这些酶的活性。尽管OA中的软骨破坏可能是由软骨细胞驱动的，但在患有该疾病的所有等级的患者中均报告了低度滑膜炎。我们早期在软骨中分析这些基因家族的工作确定了许多在OA中受调节的基因，因此这些基因与疾病过程有关。由于滑膜可能导致OA中软骨基质的破坏，我们在当前研究中扩大了筛选范围。我们分析了髋关节OA或股骨颈骨折（NOF）患者软骨和滑膜中的MMP、ADAMTS和TIMP基因，从而更全面地了解了这种疾病中的蛋白水解。与骨折的NOF相比，OA滑膜中四种最显著上调的基因（P < 0.0001）是MMP 28、ADAMTS 16、ADAMTS 17和TIMP 2。对于MMP 9、MMP 10、MMP 12、MMP 17、MMP 23、MMP 28、ADAMTS 4和ADAMTS 9，在滑膜和软骨中的表达水平之间存在显著相关性，表明了类似的调节机制。此外，我们已经表明，在软骨中，MMP 13的稳态mRNA的中值水平比MMP 28高约20倍，比ADAMTS 16高约1,500倍，后者基因在滑膜中的表达比软骨高约150倍。这项研究是迄今为止对关节中metzincin家族蛋白酶的最全面的分析，并鉴定了几种以前未报道过在滑膜中表达或调节的蛋白酶基因。
Cartilage destruction in osteoarthritis (OA) is thought to be mediated by two main enzyme families; the matrix metalloproteinases (MMPs) are responsible for cartilage collagen breakdown, whereas enzymes from the 'a disintegrin and metalloproteinase domain with thrombospondin motifs' (ADAMTS) family mediate cartilage aggrecan loss. Tissue inhibitors of metalloproteinases (TIMPs) regulate the activity of these enzymes. Although cartilage destruction in OA might be driven by the chondrocyte, low-grade synovitis is reported in patients with all grades of this disease. Our earlier work profiling these gene families in cartilage identified a number of genes that are regulated in OA, which are hence implicated in the disease process. Because the synovium might contribute to cartilage-matrix destruction in OA, we have extended the screening in the current study. We have profiled MMP, ADAMTS and TIMP genes in both cartilage and synovium from patients with either OA of the hip or a fracture to the neck of femur (NOF), giving a more complete picture of proteolysis in this disease. The four most significantly upregulated genes (P < 0.0001) in OA synovium compared to the fractured NOF are MMP28, ADAMTS16, ADAMTS17 and TIMP2. For MMP9, MMP10, MMP12, MMP17, MMP23, MMP28, ADAMTS4, and ADAMTS9, there is a significant correlation between expression levels in the synovium and cartilage, suggesting similar mechanisms of regulation. Additionally, we have shown that in cartilage the median level of steady-state mRNA for MMP13 is approximately 20-fold higher than MMP28 and approximately 1,500-fold higher than ADAMTS16, with expression of this latter gene approximately 150-fold higher in synovium than cartilage. This study is the most comprehensive analysis of the metzincin family of proteinases in the joint to date and has identified several proteinase genes not previously reported to be expressed or regulated in synovium.