ADAMTS4 and ADAMTS5 knockout mice are protected from versican but not aggrecan or brevican proteolysis during spinal cord injury.
ADAMTS4 and ADAMTS5 knockout mice are protected from versican but not aggrecan or brevican proteolysis during spinal cord injury.
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DOI：
10.1155/2014/693746
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发表时间：
2014
影响因子：
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通讯作者：
Hirohata S
中科院分区：
文献类型：
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作者：
Demircan K;Topcu V;Takigawa T;Akyol S;Yonezawa T;Ozturk G;Ugurcu V;Hasgul R;Yigitoglu MR;Akyol O;McCulloch DR;Hirohata S
硫酸软骨素蛋白聚糖（CSPG）聚集蛋白聚糖（aggrecan）、多功能蛋白聚糖（versican）和短蛋白聚糖（brevican）是抑制成熟中枢神经系统（CNS）的轴突生长的大的聚集性细胞外基质分子。ADAMTS蛋白聚糖酶，包括ADAMTS 4和ADAMTS 5，降解CSPG，代表改善CNS损伤后CSPG积累对轴突生长抑制的潜在靶点。我们研究了脊髓损伤（SCI）后Adamts 4或Adamts 5无效等位基因纯合子小鼠中CSPG的蛋白水解。在Adamts 4-/-、Adamts 5-/-和wt小鼠中观察到ADAMTS衍生的50-60 kDa聚集蛋白聚糖和50 kDa短蛋白聚糖片段，但在假手术组中未观察到。相比之下，Adamts 4 −/−和Adamts 5 −/−小鼠均受到多功能蛋白聚糖蛋白水解的保护，其中ADAMS产生的70 kDa多功能蛋白聚糖片段主要在WT小鼠中观察到。通过Western blot检测SCI后Adamts 4 −/−小鼠脊髓中的ADAMTS 1、ADAMTS 9和ADAMTS 15。免疫组化显示星形胶质细胞在损伤部位聚集。这些数据表明，在Adamts 4-/-或Adamts 5-/-小鼠中，ADAMTS蛋白聚糖酶家族成员补偿了聚集蛋白聚糖和短蛋白聚糖的蛋白水解，但多功能蛋白聚糖蛋白水解的阈值对SCI期间单个ADAMTS蛋白聚糖酶的丢失敏感。我们在SCI后显示出强大的ADAMTS活性，并证实了SCI期间有效清除CSPG需要集体蛋白水解。
The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50–60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4−/−, Adamts5−/−, and wt mice but not in the sham-operated group. By contrast Adamts4−/− and Adamts5−/− mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4−/− mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4−/− or Adamts5−/− mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.