Remodeling of ECM as well as excessive ECM production are important factors in the process of tissue fibrosis. Remodeling of ECM is largely affected by the activities of proteinases that can degrade matrix, such as MMPs and their inhibitor, TIMP.
39,40 There is excellent evidence in both human liver disease and animal models, indicating that hepatic fibrosis is potentially reversible.
41 Decline in TIMP levels, which tips the overall MMP–TIMP balance toward MMP, results in increased matrix degradation and net degradation of scar tissue.
42,43 However, very few studies have investigated tissue remodeling in GO. Han et al.
44 reported that IL-1β treatment of orbital fibroblasts increases TIMP-1 expression, thus disrupting the balance between MMPs and TIMP. Additionally, treatment with antioxidants decreases the levels of MMPs and TIMP-1.
34,45 The results of the present study demonstrated that IL-1β increases MMP-2, MMP-9, and TIMP-1 expression in GO orbital fibroblasts, which is concordant with the findings of previous studies.
34,46 Since treatment with W146, JTE013, FTY720, and 5C resulted in the downregulation of IL-1β–induced expression of MMP-1, MMP-2, MMP-9, and TIMP-1, we believe that S1P might act as a mediator of inflammation-induced tissue remodeling. Additionally, since exogenous S1P treatment increased the expression of MMP-1, MMP-2, MMP-9, and TIMP-1, we assume that S1P also has a direct effect on stimulation of tissue remodeling. Matrix metalloproteinase-1, also known as interstitial collagenase, degrades fibrillar collagen types I, II, and III, which are major components of the ECM.
39 However, to date, expression of tissue remodeling proteins in GO orbital fibroblasts has only been reported in relation to TIMP-1, MMP-2, and MMP-9.
34,44,45 The present results demonstrate that IL-1β stimulation can induce MMP-1 expression in GO orbital fibroblasts and that S1P is involved in this induction process. It is possible that S1P-mediated upregulation or S1PR blocker–mediated suppression of collagen Iα and MMP-1 expression are related; however, this aspect has not been investigated in this study. Further confirmation of related pathways is necessary. Moreover, MMP expression varies depending on the organ, and while some MMPs are indeed antifibrotic, others might have profibrotic functions.
40 For example, in the kidney, MMP-9 has profibrotic activity, while MMP-2 has an antifibrotic function.
47,48 Therefore, detailed studies on elucidating the function of MMPs in orbital fibroblasts are required.