Agah Azin, Kyriakides Themis R, Letrondo Nikole, Björkblom Benny, Bornstein Paul
Departments of Biochemistry, University of Washington, Box 357350, Seattle, WA 98195, USA.
Matrix Biol. 2004 Jan;22(7):539-47. doi: 10.1016/j.matbio.2003.09.004.
The inhibitor of angiogenesis, thrombospondin 2 (TSP2), belongs to a group of matricellular proteins that are induced in response to injury and modulate the healing of dermal wounds. Thus, TSP-2-null mice display abnormal connective tissue architecture and increased angiogenesis in the dermis, and heal wounds at an accelerated rate. In this study, we report that the content of TSP2 is increased in the uninjured skin of aged mice. Furthermore, in primary dermal fibroblasts, TSP2 expression is increased both as a function of the age of the donor and days in culture. To determine the significance of the increased TSP2 in aged mice (two years or older), we performed full-thickness excisional wounds and compared their healing in aged and young (3-4 months) wild-type and TSP2-null mice. Gross morphological examination of wounds indicated that aged TSP2-null mice healed faster than their aged wild-type counterparts, but healing in aged mice was always sub-optimal in comparison to that in young animals. Surprisingly, despite the increase in TSP2, a potent inhibitor of angiogenesis, in wounds in aged mice, the vascular density of these wounds was not reduced in comparison to that in young animals. However, immunohistochemical analysis of healing wounds revealed a shift in the peak content of TSP2, from day 10 in young mice to day 14 or later in aged mice, and there was a corresponding delay in the expected increase in matrix metalloproteinase (MMP) 2 levels in aged TSP2-null mice. We suggest that the delay in expression of TSP2 and MMP2 in the wounds of aged mice could contribute to their impaired rate of wound healing.
血管生成抑制剂血小板反应蛋白2（TSP2）属于一组基质细胞蛋白，这些蛋白在受到损伤时被诱导产生，并调节皮肤伤口的愈合。因此，TSP - 2基因敲除小鼠表现出异常的结缔组织结构，真皮中的血管生成增加，且伤口愈合速度加快。在本研究中，我们报告了老年小鼠未受伤皮肤中TSP2的含量增加。此外，在原代表皮成纤维细胞中，TSP2的表达随着供体年龄和培养天数的增加而增加。为了确定老年小鼠（两岁及以上）中TSP2增加的意义，我们进行了全层切除伤口实验，并比较了老年和年轻（3 - 4个月）野生型及TSP2基因敲除小鼠的伤口愈合情况。伤口的大体形态学检查表明，老年TSP2基因敲除小鼠的伤口愈合速度比其老年野生型同窝小鼠快，但与年轻动物相比，老年小鼠的伤口愈合总是不太理想。令人惊讶的是，尽管老年小鼠伤口中血管生成的强效抑制剂TSP2有所增加，但与年轻动物相比，这些伤口的血管密度并未降低。然而，对愈合伤口的免疫组织化学分析显示，TSP2的峰值含量出现了变化，从年轻小鼠的第10天推迟到老年小鼠的第14天或更晚，并且老年TSP2基因敲除小鼠中基质金属蛋白酶（MMP）2水平预期的增加也相应延迟。我们认为，老年小鼠伤口中TSP2和MMP2表达的延迟可能导致其伤口愈合速度受损。
