Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

Abstract

Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.

Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells

“…The measurement of BRD9 expression was conducted in relatively small samples. UF heterogeneity occurs at many levels, including etiology, clinical symptoms, and pathogenesis, significantly impacting research design and therapeutic decisions [45]. In this study, we observed the variation of BRD9 expression in UFs.…”

“…The results were consistent with the RNA-seq data (Figure S3A). Several studies have demonstrated that abnormal ECM accumulation and remodeling are critical for UFs [42][43][44][45]. Excessive ECM deposition and production can contribute to mechanotransduction, therefore regulating downstream signaling leading to the pathogenesis of UFs [46][47][48].…”

The Influence of Race/Ethnicity on the Transcriptomic Landscape of Uterine Fibroids

“…The next group of genes (KRT17, COL24A1, MMP17, MYOG, MYO5B, and GRIP1) with minimal to no alteration in matched myometrium in the White patients but with significantly higher expression in fibroids from Black and Hispanic patients were related to the cell cytoskeleton and ECM. One of the hallmark characteristics of fibroid tumors is the excess ECM production, which contributes to its stiffness [85][86][87]. The ECM is a reservoir of growth factors and cytokines, and changes in ECM stiffness result in signals that are converted into chemical changes [85].…”

Occurrence and Risk Factors for Perioperative Treatment Discontinuation during Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU) Therapy in Symptomatic Uterine Fibroids—A Retrospective Case–Control Study

“…Several mechanisms are proposed to explain the development and growth of UFs. Sex hormones, molecular changes in the extracellular matrix, growth factors, epigenetic and epitranscriptomic regulation and DNA damage repair pathways seem to play the most crucial role [ 3 , 4 ]. The problem of UFs is faced by up to 70% of women at menopausal age.…”