Pirilä Emma, Parikka Mataleens, Ramamurthy Nungavarm S, Maisi Päivi, McClain Steve, Kucine Allan, Tervahartiala Taina, Prikk Kaiu, Golub Lorne M, Salo Tuula, Sorsa Timo
Department of Clinical Veterinary Sciences, University of Helsinki, Finland.
Wound Repair Regen. 2002 Jan-Feb;10(1):38-51. doi: 10.1046/j.1524-475x.2002.10605.x.
Estrogen deficiency is associated with impaired cutaneous wound healing. Remodeling of the extracellular matrix in wound healing involves the action of matrix metalloproteinases on basement membrane zone components, especially laminin-5. We studied the effects of estrogen and a potent matrix metalloproteinase inhibitor, chemically modified non-antimicrobial tetracycline, CMT-8, on wound healing in ovariectomized rats. At the tissue level, laminin-5 gamma2-chain expression was decreased and the migration-inductive 80 kDa form of laminin-5 gamma2-chain was absent in ovariectomized rats when compared with sham and CMT-8- or estrogen-treated ovariectomized animals as detected by Western blotting. The highest levels of gelatinolytic activity (matrix metalloproteinase-2 and -9) were found in sham animals. Levels were reduced in ovariectomized rats and were lowest after treating ovariectomized rats with CMT-8 or estrogen as analyzed by functional activity assay and zymography. The total amount of membrane type 1-matrix metalloproteinase was unchanged in all groups. We conclude that CMT-8 and estrogen can promote wound healing in ovariectomized rats, not only by normalizing wound bed total collagen content and structure, but also by recovering the expression and processing of key molecules in wound healing, i.e., laminin-5 gamma2-chain. This study shows, for the first time, the role of estrogen and CMT-8 in laminin-5 gamma2-chain modulation in vivo.
雌激素缺乏与皮肤伤口愈合受损有关。伤口愈合过程中细胞外基质的重塑涉及基质金属蛋白酶对基底膜区成分的作用，尤其是层粘连蛋白-5。我们研究了雌激素和一种强效基质金属蛋白酶抑制剂——化学修饰的非抗菌四环素（CMT-8）对去卵巢大鼠伤口愈合的影响。在组织水平上，通过蛋白质印迹法检测发现，与假手术组以及CMT-8或雌激素处理的去卵巢动物相比，去卵巢大鼠中层粘连蛋白-5γ2链的表达降低，且不存在具有迁移诱导作用的80 kDa形式的层粘连蛋白-5γ2链。假手术组动物的明胶酶活性（基质金属蛋白酶-2和-9）水平最高。通过功能活性测定和酶谱分析发现，去卵巢大鼠的酶活性水平降低，在用CMT-8或雌激素处理去卵巢大鼠后酶活性水平最低。所有组中膜型1-基质金属蛋白酶的总量没有变化。我们得出结论，CMT-8和雌激素可以促进去卵巢大鼠的伤口愈合，不仅通过使伤口床总胶原蛋白含量和结构正常化，还通过恢复伤口愈合关键分子即层粘连蛋白-5γ2链的表达和加工。本研究首次展示了雌激素和CMT-8在体内对层粘连蛋白-5γ2链调节中的作用。
