Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis
Double-knockout of ADAMTS-4 and ADAMTS-5 in mice results in physiologically normal animals and prevents the progression of osteoarthritis
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DOI：
10.1002/art.23027
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发表时间：
2007-11-01
影响因子：
--
通讯作者：
Glasson, Sonya S.
中科院分区：
文献类型：
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作者：
Majumdar, Manas K.;Askew, Roger;Glasson, Sonya S.
Objective.研究ADAMTS-4和ADAMTS-5双基因敲除小鼠的表型特征，并确定ADAMTS-4和ADAMTS-5基因敲除对小鼠骨关节炎（OA）进展的影响。将缺乏ADAMTS-4和ADAMTS-5的催化结构域的小鼠杂交以产生ADAMTS-4/5双敲除动物。通过评价终末体重、器官重量、临床病理学参数、PIXImus小鼠光密度测定结果以及肉眼和显微镜观察结果，将10周龄和1岁雄性和雌性ADAMTS-4/5双敲除小鼠与年龄和性别匹配的野生型（WT）小鼠进行比较。ADAMTS-4/5-双敲除小鼠通过手术诱导关节不稳定性进行攻击，以确定这些基因在OA进展中的重要性。将来自WT和ADAMTS-4/5双敲除小鼠的关节和非关节软骨外植体用白细胞介素-1（IL-1）加维甲酸离体处理，以检测蛋白多糖降解。在1岁内，ADAMTS-4/5双敲除小鼠和WT小鼠之间没有基因型相关的表型差异，除了雌性ADAMTS-4/5双敲除小鼠在12周时间点的平均终末体重较低。手术诱导关节不稳定8周后，与W小鼠相比，ADAMTS-4/5双敲除小鼠的OA严重程度显著降低。在用IL-1加视黄酸刺激软骨外植体后，ADAMTS-4/5双敲除小鼠中聚集蛋白聚糖酶介导的降解被消除，达到与ADAMTS-5敲除小鼠相当的水平。ADAMTS-4和ADAMTS-5的双重缺失产生的小鼠在表型上与WT小鼠无法区分。ADAMTS-4/5的缺失提供了对离体蛋白聚糖降解的显著保护，并降低了小鼠OA的严重程度。ADAMTS-4/5双敲除小鼠中的这些效应与单独缺失ADAMTS-5所观察到的效应相当。
Objective. To phenotypically characterize ADAMTS-4- and ADAMTS-5-double-knockout mice, and to determine the effect of deletion of ADAMTS-4 and ADAMTS-5 on the progression of osteoarthritis (OA) in mice.Methods. Mice lacking the catalytic domain of ADAMTS-4 and ADAMTS-5 were crossed to generate ADAMTS-4/5-double-knockout animals. Twelve-week-old and 1-year-old male and female ADAMTS-4/5-double-knockout mice were compared with age- and sex-matched wild-type (WT) mice by evaluating terminal body weights, organ weights, clinical pathology parameters, PIXImus mouse densitometry findings, and macroscopic and microscopic observations. ADAMTS-4/5-double-knockout mice were challenged by surgical induction of joint instability to determine the importance of these genes in the progression of OA. Articular and nonarticular cartilage explants from WT and ADAMTS-4/5-double-knockout mice were treated with interleukin-1 (IL-1) plus retinoic acid ex vivo, to examine proteoglycan degradation.Results. There were no genotype-related phenotype differences between ADAMTS-4/5-double-knockout and WT mice through 1 year of age, with the exception that female ADAMTS-4/5-double-knockout mice had a lower mean terminal body weight at the 12-week time point. Eight weeks after surgical induction of joint instability, OA was significantly less severe in ADAMTS-4/5-double-knockout mice compared with W mice. Following stimulation of cartilage explants with IL-1 plus retinoic acid, aggrecanase-mediated degradation in ADAMTS-4/5double-knockout mice was ablated, to a level comparable with that in ADAMTS-5-knockout mice.Conclusion. Dual deletion of ADAMTS-4 and ADAMTS-5 generated mice that were phenotypically indistinguishable from WT mice. Deletion of ADAMTS-4/5 provided significant protection against proteoglycan degradation ex vivo and decreased the severity of murine OA. These effects in the ADAMTS-4/5-double-knockout mice were comparable with those observed with deletion of ADAMTS-5 alone.