Abstract
The function of cyclophilin C-associated protein (CyC-AP) on expression of extracellular matrix and matrix metalloproteinases (MMPs) was studied in CyC-AP-null mice. Fibronectin showed increased expression of the 53- and 29-kDa fragments in skin and wounds from CyC-AP-null mice. Type I collagen had an initial degraded pattern in the skin of CyC-AP-null mice, which did not occur in wild-type mice. MMP-3, MMP-13, MMP-14, and tumor necrosis factor-alpha (TNFalpha) had a higher expression in CyC-AP-null skin. During wound healing, MMP-13 and TNFalpha were stimulated to an even higher level, suggesting they are regulated by multiple factors. To understand the regulatory mechanisms of the up-regulated MMPs, the direct effects of TNFalpha, IL-1beta, 45-kDa fibronectin fragment (FN-45), and the 70-kDa fibronectin fragments (FN-70) on the expression of MMPs were studied. MMP-13 expression increased significantly in both CyC-AP-null and wild-type dermal fibroblasts after treatment with IL-1beta or with TNFalpha. However, MMP-13 expression did not increase in CyC-AP-null fibroblasts but did increase only in wild-type fibroblasts after FN-45 and FN-70 treatment. MMP-3 activation was induced by FN-45 and did not show a difference between CyC-AP-null and wild-type fibroblasts, suggesting different regulatory pathways for FN-45 on MMP-13 and MMP-3 expression. Our data are the first to demonstrate that deletion of CyC-AP can abolish fibronectin fragment-induced MMP-13 expression through an unknown mechanism. CyC-AP is an important factor for the regulation of MMP-13 expression.
Highlights
Growth and reproductive abilities, have lower survival rates after endotoxin exposure, suggesting that cyclophilin C-associated protein (CyC-AP) can downregulate, or provide negative feedback, that limits the induced inflammatory response
We report that the expression of the 53 and 29 kDa fibronectin fragments, matrix metalloproteinases (MMPs)-3, MMP-13, MMP-14, as well as TNF␣, is significantly higher in both unwounded and wounded skin in CyC-AP-null mice
The expression of MMP-3 and MMP-13 was higher in both pro- and activated form in the skin of CyC-AP-null mice compared with wild-type; the expression of MMP-3 and MMP-13 was further increased during wound repair in CyC-AP-null skin
Summary
Growth and reproductive abilities, have lower survival rates after endotoxin exposure, suggesting that CyC-AP can downregulate, or provide negative feedback, that limits the induced inflammatory response. Some reports have suggested that Mac-2 BP may be an adhesive protein of extracellular matrix (ECM). Among the ECM proteins, Mac-2 BP has been shown to have highest binding affinity to fibronectin [7]. The gelatin-binding fibronectin fragments, sizes 110 kDa and 45 kDa, induce MMP-13 synthesis in chondrocytes [21, 22]. The C-terminal heparin-binding fibronectin fragment increases the release of MMP-1, -3, and -13 [23]. The 29-kDa N-terminal fibronectin fragment has been reported to have potent chondrolytic activity [24]. Serotonin induces MMP-13 by protein kinase C and extracellular signal-regulated pathway 1/2 MAP kinase pathways [18], while tumor growth factor  operates through the p38 MAP kinase pathway [17]. Blocking antibodies to integrins ␣21 and ␣51 increases MMP-13 production through the same pathway as IL-1 [28]
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