A Matrix Metalloproteinase-9 Activation Cascade by Hepatic Stellate Cells in Trans-differentiation in the Three-dimensional Extracellular Matrix

摘要: Hepatic stellate cells (HSCs) undergo myofibroblastic trans-differentiation in liver fibrogenesis. We previously showed that dual stimulation with three-dimensional type-I collagen and interleukin-1 (IL-1) synergistically induces HSC a manner dependent on the activation of matrix metallopreinase-9 (MMP-9). The present study is aimed to determine mechanism MMP-9 this model. pro-MMP-9-converting activities expressed by trans-differentiating HSCs are characterized as secreted factors sensitive MMP inhibitor have apparent molecular masses 50 25 kDa. This sharp contrast pro-MMP-9 activator from mouse human skin, which chymotrypsin-like proteinase. Among multiple MMPs induced stimulation, MMP-13 most conspicuously up-regulated meets all criteria activator. cultured collagen, but not Matrigel, IL-1 expression its matured form at kDa, respectively. In vitro reconstitution experiment proves MMP-13, zymogen, activates pro-MMP-9. Further, short hairpin RNA targeting abolishes trans-differentiation. further demonstrate pro-MMP-13 facilitated membrane-associated factor, inhibited tissue metalloproteinase-2, abolished against MMP-14. Moreover, also activated absorbed gelatin-Sepharose reconstituted MMP-9. Thus, IL-1-induced extracellular an cascade (MMP-14 > MMP-9) positive feedback loop suggesting their critical roles injury repair.