Settle Steven, Vickery Lillian, Nemirovskiy Olga, Vidmar Tom, Bendele Alison, Messing Dean, Ruminski Peter, Schnute Mark, Sunyer Teresa
Pfizer Global Research and Development, St. Louis, Missouri, USA.
Arthritis Rheum. 2010 Oct;62(10):3006-15. doi: 10.1002/art.27596.
To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP-13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation.
The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS-4 and ADAMTS-5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis.
The potent and selective MMP-13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose-dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results.
This highly selective MMP-13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP-13 inhibitor. These data support the potential therapeutic value of selective MMP-13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.
证明新型高选择性基质金属蛋白酶13（MMP - 13）抑制剂PF152可减轻成年骨关节炎（OA）犬的关节损伤，并降低软骨降解生物标志物水平。
在体外使用16种基质金属蛋白酶、肿瘤坏死因子α转换酶（TACE）、含血小板反应蛋白基序的解聚素样金属蛋白酶4（ADAMTS - 4）和含血小板反应蛋白基序的解聚素样金属蛋白酶5（ADAMTS - 5）评估PF152的效力和选择性，并在人软骨外植体中进行离体评估。在成熟的比格犬身上进行内侧半月板部分切除术，以3种浓度评估PF152的体内效应。使用各种软骨退变测量方法评估股骨胫关节的大体和组织学变化。在血清、尿液或滑液中检测软骨周转生物标志物。使用多变量分析单独和综合分析结果。
强效且选择性的MMP - 13抑制剂PF152在体外以剂量依赖性方式减少人软骨降解。用PF152治疗OA犬可减少软骨损伤，并降低II型胶原蛋白（II型胶原新表位）和聚集蛋白聚糖（以ARGN或AGEG结尾的肽段）降解的生物标志物水平。显著抑制所需的剂量因所用测量方法而异，但对6种大体和组织学测量方法进行多变量分析表明，所有剂量与赋形剂相比均有显著差异，但彼此之间无显著差异。软骨降解标志物的综合分析显示了类似结果。
这种高选择性MMP - 图13抑制剂在成熟动物中表现出软骨保护作用。综合评估时，软骨降解生物标志物与MMP - 13抑制剂诱导的关节结构变化平行。这些数据支持选择性MMP - 13抑制剂的潜在治疗价值，以及使用一组合适的生物标志物来预测OA临床试验中的疗效。
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