Interleukin-1β activated c-FOS transcription factor binds preferentially to a specific allele of the matrix metalloproteinase-13 promoter and increases susceptibility to endometriosis.

Abstract

Endometriosis is a benign gynecological condition characterized by increased growth, inflammation, invasion, and angiogenesis, partly regulated by a class of enzymes called matrix metalloproteinases (MMPs). The importance of a few MMPs, e.g., MMP-9, -3, and -7 has been studied in endometriosis progression. Although MMP-13 plays an essential role in bone regeneration and cancer, no report has been found on the part of MMP-13 and endometriosis progression. We found the upregulation of MMP-13 expression and activity in patients having endometriosis in the eastern Indian population. In addition, the -77A/G polymorphism of the MMP13 promoter (rs: 2252070) is associated with regulating transcription and subsequent susceptibility to disease. In eastern Indian case-control groups, the effect of the -77A/G single-nucleotide polymorphism on MMP13 promoter activity and its relationship with endometriosis susceptibility was studied. The AG genotype was shown to be more predisposed to endometriosis risk than the GG genotype (p:0.02; odds ratio [OR]: 1.65, 95% confidence interval [CI]: 1.10-2.49), also AG genotype was more frequent in late-stage patients compared to early-stage (p: 0.03, OR: 2.0, 95% CI: 1.09-3.66). Furthermore, the MMP13 gene levels were greater in AA compared to GG individuals. Additionally, MMP13 promoter-reporter experiments in cultured endometrial epithelial cells and in silico analyses both demonstrated increased transcriptional activity near the G to A transition under basal/IL-1β -induced/c-FOS overexpressed condition. Overall, c-FOS tighter binding to the A allele-carrying promoter enhances MMP13 transcription, which is further amplified by IL-1β due to increased c-FOS phosphorylation, promoting MMP-13 production and endometriosis risk.