Collagen fibril disruption occurs early in primary guinea pig knee osteoarthritis
Collagen fibril disruption occurs early in primary guinea pig knee osteoarthritis
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DOI：
10.1016/j.joca.2009.09.011
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发表时间：
2010-03-01
影响因子：
7
通讯作者：
Kraus, V. B.
中科院分区：
文献类型：
--
作者：
Huebner, J. L.;Williams, J. M.;Kraus, V. B.
目的：阻碍骨性关节炎(OA)结构改良剂发现的一个主要障碍是对早期疾病事件的不完全理解。方法：46只雄性Hartley豚鼠分别于3周、2、4、7、10、12、18个月龄时观察膝关节CA的组织学变化，半定量偏光显微镜观察软骨胶原原纤维断裂情况，免疫组织化学方法检测II型胶原降解标志物9A4和COL2-1的表达。结果：尽管4个月龄时出现了组织学上的骨性关节炎，但11号胶原降解、CTX-II、C2C和COL2-1的血清生物标志物在2个月龄时就观察到了胶原纤维断裂和胶原酶基因分级的裂解新表位9A4的表达。在3周到7个月之间，只有血清COL2-1的升高与胶原纤维的早期断裂一致，而血清C2C则没有显著变化，也没有与组织学严重程度相关。相反，CTX-II从3周到4个月急剧下降，此后一直保持在较低水平，与生长板翻转一致。结论：胶原酶裂解和11型胶原网络破坏是该模型CA早期的疾病事件，是蛋白多糖丢失的组织学证据。在疾病发展的早期阶段，与II型胶原相关的生物标志物的血清图谱明显不同，这表明胶原降解酶的隔室隔离和时间调节。(C)2009年国际骨性关节炎研究会。爱思唯尔有限公司出版。保留所有权利。
Objective: A major barrier inhibiting the discovery of structural modifying agents for osteoarthritis (OA) is an incomplete understanding of early disease events. Herein, we investigated the time course of collagen II cleavage and fibril disruption in the well-validated Hartley guinea pig model of spontaneous CA of the knee.Methods: Knee joints of 46 male Hartley guinea pigs were analyzed at 3 weeks, 2, 4, 7, 10, 12, and 18 months of age for histological severity of CA, cartilage collagen fibril disruption by semi-quantitative polarized light microscopy, and expression of type II collagen degradation biomarkers, 9A4 and Coll2-1, by immunohistochemistry. In addition, serum biomarkers specific for collagen 11 degradation, CTX-II, C2C, and Coll2-1 were quantified.Results: Collagen fibril disruption and expression of the collagenase-gene rated cleavage neoepitope, 9A4, were observed as early as 2 months of age, despite the appearance of histological OA at 4 months of age. Only serum Coll2-1 increased coincident with the early disruption of the collagen fibril between 3 weeks and 7 months, in contrast to serum C2C, which did not change significantly or correlate with histological severity. Inversely, CTX-II declined dramatically from 3 weeks to 4 months and remaining low thereafter, coincident with growth plate turnover.Conclusions: Collagenase cleavage and disruption of the type 11 collagen network are early CA disease events in this model, preceding histological evidence of proteoglycan loss. The markedly different serum profiles of collagen II-related biomarkers during the early stages of disease development suggest compartmental segregation and temporal regulation of collagen degrading enzymes. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.