McCulloch Daniel R, Nelson Courtney M, Dixon Laura J, Silver Debra L, Wylie James D, Lindner Volkhard, Sasaki Takako, Cooley Marion A, Argraves W Scott, Apte Suneel S
Department of Biomedical Engineering, Lerner Research Institute, ND20-Cleveland Clinic, Cleveland, OH 44195, USA.
Dev Cell. 2009 Nov;17(5):687-98. doi: 10.1016/j.devcel.2009.09.008.
We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5(-/-);bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5(-/-);bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments.
我们发现，分泌型金属蛋白酶Adamts5、Adamts20（bt）和Adamts9的组合小鼠等位基因会导致完全显性的软组织并指畸形。Adamts5（-/-）；bt/bt小鼠的指间蹼凋亡减少，蛋白聚糖多功能蛋白聚糖的裂解减少；然而，调节指间凋亡的BMP-FGF轴未受影响。BMP4诱导凋亡，但没有伴随多功能蛋白聚糖的蛋白水解。Vcan或Fbln1（ADAMTS5加工多功能蛋白聚糖的辅助因子）的单倍体不足导致bt小鼠出现高度显性的并指畸形，这表明裂解的多功能蛋白聚糖对蹼的消退至关重要。局部应用与ADAMTS加工的多功能蛋白聚糖相对应的氨基末端多功能蛋白聚糖片段，可诱导Adamts5（-/-）；bt/bt蹼中的细胞死亡。因此，ADAMTS蛋白酶协同作用，将多功能蛋白聚糖的蛋白水解维持在所需阈值以上，为凋亡创造一个允许的环境。这些数据突出了对细胞外基质进行蛋白水解作用在发育中的重要性，这不仅是一种清除机制，也是产生生物活性多功能蛋白聚糖片段的一种方式。
