Alantos Pharmaceuticals AG, Heidelberg, Germany.
Inflamm Res. 2010 May;59(5):379-89. doi: 10.1007/s00011-009-0112-9. Epub 2009 Nov 10.
MMP-13 is highly upregulated in arthritis and therefore strongly implicated in the pathogenesis of osteoarthritis (OA). Selective inhibition of MMP-13 may provide the desired cartilage degradation protection, while overcoming the musculoskeletal toxicity seen with nonselective inhibition of MMPs.
Activity and selectivity of novel MMP-13 inhibitors were determined in enzymatic and collagenase assays. Inhibition kinetics and competitive binding experiments were performed. The inhibition of collagen degradation was studied in cartilage explants from OA patients and in bovine and human articular cartilage systems.
We have identified a new class of very potent and highly selective non-zinc-binding MMP-13 inhibitors. Selective MMP-13 inhibitors completely blocked type II collagen degradation in bovine explants and showed up to 80% inhibition in human OA cartilage.
These results indicate MMP-13 as the primary collagenase in the human OA cartilage and in the IL-1/OSM-induced cartilage degradation process and suggest that selective MMP-13 inhibitors may be a potential treatment of OA.
MMP-13 在关节炎中高度上调，因此强烈参与骨关节炎（OA）的发病机制。选择性抑制 MMP-13 可能提供所需的软骨降解保护，同时克服非选择性 MMP 抑制所看到的肌肉骨骼毒性。
在酶和胶原酶测定中确定新型 MMP-13 抑制剂的活性和选择性。进行抑制动力学和竞争性结合实验。在来自 OA 患者的软骨外植体以及牛和人关节软骨系统中研究胶原降解的抑制。
我们已经确定了一类新型的非常有效且高度选择性的非锌结合 MMP-13 抑制剂。选择性 MMP-13 抑制剂完全阻止了牛外植体中 II 型胶原的降解，并在人类 OA 软骨中显示出高达 80%的抑制作用。
这些结果表明 MMP-13 是人类 OA 软骨和 IL-1/OSM 诱导的软骨降解过程中的主要胶原酶，并表明选择性 MMP-13 抑制剂可能是 OA 的一种潜在治疗方法。
