A systematic review of matrix metalloproteinases as potential biomarkers for uterine fibroids

Objective

Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases that play a critical role in morphogenesis, wound healing, and tissue repair. Uterine fibroids (UFs) are benign, fibrous smooth muscle tumors with excessive deposition of the extracellular matrix rich in interstitial collagen. This systematic review aims to rigorously assess current literature evaluating the role of MMPs in the pathoetiology of UFs.

Evidence Review

A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was conducted within PubMed, Embase, and Scopus databases. A data informationist was engaged to develop a comprehensive search strategy. Studies examining the MMP levels in leiomyoma and myometrium were searched. Two investigators independently screened and identified articles. Observational and interventional studies involving human subject research published in English up to January 2022 were included. Animal subject research, non-English articles, and reviews were excluded. The articles were assessed for risk of bias using the Newcastle-Ottawa scale. One investigator extracted the data, and a second investigator checked the accuracy. The extracted data were synthesized descriptively.

Results

The initial search yielded 235 articles. After reviewing titles, abstracts, and full texts, 30 observational studies were judged to meet the inclusion criteria. The expression levels of MMPs in leiomyomas and myometrium varied among subtypes of MMPs. Nine studies reported elevated levels of MMP-2 expression and activity in leiomyoma cells compared with those in myometrium cells, whereas 1 study found a decreased level of MMP-2 expression. Two studies reported higher mRNA levels of MMPs in the secretory phase than in the proliferative phase. Two studies examined the relationship between MMP-1, -3, -9 genotypes and leiomyoma, and no association was found. One study examined the difference in MMP expression levels among leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma and found higher MMP-2 expression in leiomyosarcoma than in leiomyoma. The effects of estradiol on MMP expression and activity levels were examined in 2 studies. One study reported an upregulation of MMP-2 expression in leiomyomas by the administration of estradiol. Another study found that estradiol decreased MMP-2 activity in leiomyoma. We also identified studies that examined the effects of selective estrogen receptor modulators, gonadotropin-releasing hormone agonists, and selective progesterone receptor modulators on MMPs expression and activity in patients with UFs.

Conclusion

Data were mostly consistent regarding the expression and activity levels of MMPs in uterine leiomyomas. All included studies were observational, and the number of participants was relatively small. Therefore, biases and random errors might exist. The function of MMPs extends beyond simply degrading and remodeling extracellular matrix; MMPs also function as signaling enzymes. However, the evidence is limited, and further investigation is needed to assess the role of MMPs in the collagen biosynthesis in leiomyomas to evaluate the pathways for the variable expression and activity levels.