Blom Arjen B, van Lent Peter L, Libregts Sten, Holthuysen Astrid E, van der Kraan Peter M, van Rooijen Nico, van den Berg Wim B
Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.
Arthritis Rheum. 2007 Jan;56(1):147-57. doi: 10.1002/art.22337.
To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP-3) in the pathology of early and late OA.
The role of synovial macrophages in MMP-mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase-induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP-3-knockout mice and control mice, by histologic assessment and VDIPEN staining.
On day 14 following induction of OA, MMP-mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean +/- SD positively stained surface area 20 +/- 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP-induced neoepitopes was largely prevented (mean +/- SD positively stained surface area 5 +/- 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMP-mediated cartilage damage. We observed a strong decrease in MMP-3 and MMP-9 expression in synovial but not cartilage tissue in macrophage-depleted joints. Among 2-year-old mice, spontaneous OA-like changes in the lining layer were significantly decreased in MMP-3-knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP-3-knockout mice. In addition, MMP-mediated VDIPEN expression was significantly decreased, indicating reduced MMP-mediated cartilage breakdown.
The results of this study prove that MMP-3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage.
探讨滑膜巨噬细胞在骨关节炎（OA）早期软骨损伤中的作用，并确定基质金属蛋白酶3（MMP-3）在OA早期和晚期病理过程中的作用。
通过在胶原酶诱导的OA不稳定模型诱发前清除滑膜巨噬细胞，研究滑膜巨噬细胞在OA中MMP介导的损伤中的作用。使用TaqMan分析监测滑膜和软骨中MMP的表达。在自发性和诱发性OA中，通过组织学评估和VDIPEN染色对MMP-3基因敲除小鼠和对照小鼠的软骨病理进行评分。
在OA诱导后第14天，在轻度实验性OA小鼠的软骨中检测到MMP介导的新表位（平均±标准差阳性染色表面积20±3.2%）。值得注意的是，通过在OA诱导前清除滑膜巨噬细胞，MMP诱导的新表位的产生在很大程度上得到了预防（平均±标准差阳性染色表面积5±1%；P<0.001），表明滑膜巨噬细胞在MMP介导的软骨损伤发生中起重要作用。我们观察到在巨噬细胞清除的关节中，滑膜组织而非软骨组织中MMP-3和MMP-9的表达显著降低。在2岁小鼠中，与对照小鼠相比，MMP-3基因敲除小鼠衬里层的自发性OA样改变明显减少。更显著的是，MMP-3基因敲除小鼠中严重软骨损伤的发生率降低了67%。此外，MMP介导的VDIPEN表达显著降低，表明MMP介导的软骨破坏减少。
本研究结果证明MMP-3参与了小鼠OA中严重软骨损伤的发生。滑膜巨噬细胞在早期MMP活性中起关键作用，并且似乎介导滑膜而非软骨中的MMP产生。
Zotero 插件