011 The effect of matrix metalloproteinases-3 on the deposition of α2AP in systemic sclerosis

Alpha2-antiplasmin (α2AP) is the major circulating inhibitor of plasmin, which plays an important role in the regulation of intravascular fibrinolysis. We previously showed that the expression of α2AP was elevated in dermal fibroblasts obtained from patients with systemic sclerosis (SSc), and α2AP is associated with the development of fibrosis in SSc. In SSc, the deposition of α2AP may play an important role in the development of fibrosis. Matrix metalloproteinases-3 (MMP-3), which is one of the extracellular matrix (ECM)-degrading enzymes is known to cause the dysfunction of α2AP by cleaving the Pro19-Leu20 peptide bond in α2AP. In the present study, we focused on MMP-3, and examined the relationship between α2AP and MMP3 in SSc. Although there is no difference in the serum levels of α2AP and MMP3 between healthy controls and SSc patients, the expression of α2AP was elevated, and the ratio of MMP-3 and tissue inhibitors of metalloproteinase-1 (TIMP-1) was decreased in SSc dermal fibroblasts. Next, we examined the effect of MMP-3 on the deposition of α2AP in SSc dermal fibroblast, and showed that MMP-3 promoted the degradation of α2AP and reversed a profibrotic phenotype of SSc dermal fibroblasts. Furthermore, we showed that microRNA-29a (MiR-29a), which reduces TIMP-1 production attenuated the SSc-induced α2AP expression. Our findings suggest that MMP-3 plays a pivotal role on the α2AP-associated dermal fibrosis, and might contribute to a novel therapeutic approach for SSc.