Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice
Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice
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DOI：
10.1002/art.20558
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发表时间：
2004-08-01
影响因子：
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通讯作者：
Morris, EA
中科院分区：
文献类型：
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作者：
Glasson, SS;Askew, R;Morris, EA
Objective.为了确定ADAMTS-4的酶活性在正常生长和发育中的重要性，并评估ADAMTS-4在骨关节炎（OA）进展中的作用。我们产生了催化结构域缺失的ADAMTS-4转基因小鼠，并进行了广泛的各种器官的大体和组织学分析。通过手术诱导导致OA的关节不稳定来激发小鼠，以确定ADAMTS-4的酶活性在疾病进展中的重要性。观察野生型（WT）和ADAMTS-4基因敲除（ADAMTS-4-KO）关节软骨对白细胞介素-1和维甲酸刺激的反应。在检查的36个组织部位中，1岁以下的ADAMTS-4-KO小鼠未表现出大体或组织学异常。尽管有证据表明ADAMTS-4在WT小鼠生长板中表达和活性，但这种蛋白酶的催化沉默不会导致骨骼发育，生长或重塑异常。在手术诱导关节不稳定后4周或8周，ADAMTS-4基因敲除对OA的进展或严重程度没有影响。ADAMTS-4-KO小鼠关节软骨暴露于炎性细胞因子后，聚集蛋白聚糖在TEGE（373-374）ARGS位点的酶促裂解明显。虽然ADAMTS-4基因的表达已被发现在整个身体的许多组织中，酶活性的删除似乎没有任何影响正常的生长和生理。我们的研究提供的证据表明，ADAMTS-4是主要的聚集蛋白聚糖酶在小鼠生长板，然而，删除其酶活性并不影响正常的长骨重建。我们的研究结果还导致了这样的假设，即在小鼠中，ADAMTS-4不是负责在TEGE（373-374）ARGS位点的聚集蛋白聚糖降解的主要酶。阐明ADAMTS-4在人类OA病理过程中的相对重要性需要检查人类OA组织和治疗干预后患者疾病改变的证据。
Objective. To determine the importance of the enzymatic activity of ADAMTS-4 in normal growth and development and to evaluate the role of ADAMTS-4 in the progression of osteoarthritis (OA).Methods. We generated catalytic domain-deleted ADAMTS-4-transgenic mice and performed extensive gross and histologic analyses of various organs. The mice were challenged by surgical induction of joint instability leading to OA, to determine the importance of the enzymatic activity of ADAMTS-4 in the progression of the disease. The response of wild-type (WT) and ADAMTS-4-knockout (ADAMTS-4-KO) articular cartilage to interleukin-1 and retinoic acid challenge in vitro was also evaluated.Results. ADAMTS-4-KO mice up to 1 year of age exhibited no gross or histologic abnormalities in 36 tissue sites examined. Despite evidence of ADAMTS-4 expression and activity in growth plates of WT mice, catalytic silencing of this proteinase caused no abnormalities in skeletal development, growth, or remodeling. There was no effect of ADAMTS-4 knockout on the progression or severity of OA 4 weeks or 8 weeks after surgical induction of joint instability. Enzymatic cleavage of aggrecan at the TEGE(373-374)ARGS site was clearly evident after exposure of articular cartilage from ADAMTS-4-KO mice to inflammatory cytokines.Conclusion. Although expression of the ADAMTS-4 gene has been found in many tissues throughout the body, deletion of enzymatic activity did not appear to have any effect on normal growth and physiology. Our study provides evidence that ADAMTS-4 is the primary aggrecanase in murine growth plates; however, deletion of its enzymatic activity did not affect normal long bone remodeling. Our results also lead to the hypothesis that, in the mouse, ADAMTS-4 is not the primary enzyme responsible for aggrecan degradation at the TEGE(373-374) ARGS site. The elucidation of the relative importance of ADAMTS-4 in the pathologic process of human OA will require examination of human OA tissues and evidence of disease modification in patients following therapeutic intervention.