Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair
Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair
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DOI：
10.1172/jci30765
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发表时间：
2007-06-01
影响因子：
15.9
通讯作者：
Fosang, Amanda J.
中科院分区：
文献类型：
--
作者：
Little, Christopher B.;Meeker, Clare T.;Fosang, Amanda J.
关节软骨中聚集素的丢失是由蛋白聚糖酶介导的。Aggrecanase优先切割硫酸软骨素-2(CS-2)结构域，其次是球间结构域(IGD)中的E(373下箭头374)A键。然而，IGD裂解可能对软骨生物力学更有害，因为它释放了聚集素的整个含有CS的部分。最近的研究发现，小鼠软骨中的聚集聚糖酶-2(ADAMTS-5)是主要的聚集聚糖酶，但并没有区分IGD的聚集聚糖酶和CS-2结构域的聚集聚糖酶。为了评估这种特定的切割对软骨病理的作用，我们用一种突变产生了aggrecan敲击小鼠，这种突变只使IGD对侵袭酶产生抗药性。敲门小鼠是活的和有生育能力的。无论是用ADAMTS-5消化还是用IL-1α处理软骨外植体培养的软骨，在敲击小鼠的原位软骨中均未检测到Aggrecanase的裂解。阻断IGD中的裂解不仅可以减少手术引起的骨性关节炎和炎性关节炎模型中的聚集素丢失和软骨侵蚀，而且似乎还能刺激急性炎症后的软骨修复。我们的结论是，阻止聚集蛋白IGD中的聚集溶解单独可以保护软骨免受侵蚀，并可能加强软骨修复。
Aggrecan loss from cartilage in arthritis is mediated by aggrecanases. Aggrecanases cleave aggrecan preferentially in the chondroitin sulfate-2 (CS-2) domain and secondarily at the E(373 down arrow 374)A bond in the interglobular domain (IGD). However, IGD cleavage may be more deleterious for cartilage biomechanics because it releases the entire CS-containing portion of aggrecan. Recent studies identifying aggrecanase-2 (ADAMTS-5) as the predominant aggrecanase in mouse cartilage have not distinguished aggrecanolysis in the IGD from aggrecanolysis in the CS-2 domain. We generated aggrecan knockin mice with a mutation that rendered only the IGD resistant to aggrecanases in order to assess the contribution of this specific cleavage to cartilage pathology. The knockin mice were viable and fertile. Aggrecanase cleavage in the aggrecan IGD was not detected in knockin mouse cartilage in situ nor following digestion with ADAMTS-5 or treatment of cartilage explant cultures with IL-la. Blocking cleavage in the IGD not only diminished aggrecan loss and cartilage erosion in surgically induced osteoarthritis and a model of inflammatory arthritis, but appeared to stimulate cartilage repair following acute inflammation. We conclude that blocking aggrecanolysis in the aggrecan IGD alone protects against cartilage erosion and may potentiate cartilage repair.