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Yang, Q.; Al-Hendy, A. Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids. Encyclopedia. Available online: https://encyclopedia.pub/entry/43121 (accessed on 08 July 2025).
Yang Q, Al-Hendy A. Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids. Encyclopedia. Available at: https://encyclopedia.pub/entry/43121. Accessed July 08, 2025.
Yang, Qiwei, Ayman Al-Hendy. "Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids" Encyclopedia, https://encyclopedia.pub/entry/43121 (accessed July 08, 2025).
Yang, Q., & Al-Hendy, A. (2023, April 17). Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids. In Encyclopedia. https://encyclopedia.pub/entry/43121
Yang, Qiwei and Ayman Al-Hendy. "Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids." Encyclopedia. Web. 17 April, 2023.
Regulatory Mechanism of Extracellular Matrix in Uterine Fibroids
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24065778

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. 

uterine fibroids extracellular matrix stiffness

1. Introduction

Uterine fibroids (UFs), also known as leiomyomas or myomas, 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 [1][2][3]. Each year, approximately 300,000 myomectomies and 200,000 hysterectomies are performed in the United States to remove either leiomyoma tumors or the whole uterus [4][5]. Accordingly, the annual USA healthcare costs associated with UFs have been estimated at ~34 billion USD. Therefore, UFs represent significant societal health and financial burdens.
Several risk factors have been shown to impact UF pathogenesis and are associated with a higher probability of UF formation and development. These factors include race, age, parity, family history, food additives, obesity, vitamin D deficiency, and endocrine-disrupting chemical exposure [1][6]. These risk factors affect several key pathways, including inflammation [7][8][9], DNA damage repair pathway, β-catenin pathway, and genetic instability, among others, leading to the pathogenesis of UFs [10][11][12]. Despite the importance to women’s health, there are currently no UF-specific therapeutics because UFs are heterogeneous in composition and size among women, even within the same individual, and vary in number between individuals [13][14][15][16]. These irregularities highlight the challenge of preventing UFs and treating patients with UFs. Moreover, the understanding of the origin and pathogenesis of UFs continues to evolve.

2. Extracellular Matrix and Regulation in Uterine Fibroids

Excessive extracellular matrix (ECM) accumulation and aberrant remodeling are crucial for fibrotic diseases. An increased stiffness characterizes the fibrotic microenvironment, and this rigidity is associated with disease progression. The mechanical network of fibrotic ECM is regulated by ECM-degrading enzymes called matrix metalloproteinases (MMPs). MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are often secreted in an inactive pro-MMP form, which is cleaved to the active form by various proteinases, including other MMPs. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling [17]. UFs are characterized by the excessive deposition of ECM proteins, such as collagens, fibronectin, and proteoglycans, representing fibrosis [18][19][20]. In addition to MMPs and TIMPs, several factors impact ECM accumulation and deposition in UFs.

2.1. ECM and Hormones

UFs are considered hormone-dependent tumors, based on their association with reproductive age. Estrogen and progesterone are considered the principal promoters of UF growth [1][21][22]. Estrogen-related signaling impacts the biological process via genomic and nongenomic mechanisms. In addition, estrogen is capable of inducing the expression of the progesterone receptor (PR), stimulating progesterone-regulated signaling. Estrogen exerts multiple stimulatory actions on its target cells and accelerates collagen biosynthesis [23][24]. Three-dimensional UF cell cultures exposed to estrogen and medroxyprogesterone acetate (MPA) increased in their expression of collagen I and fibronectin [25].
FK506-binding protein 51 (FKBP51) is known as a chaperone that regulates the responsiveness of steroid hormone receptors. It was linked to several intracellular pathways related to tumorigenesis and chemoresistance [26][27]. FKBP51 was shown to bind PR, glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. It was reported that FKBP51 expression is higher in UFs compared to myometrial tissues. The knockdown of FKBP51 displayed decreased mRNA levels of ECM, TIMP1, and TIMP3, and reduced cell proliferation [28].
Prolactin is a hormone responsible for lactation and has been reported to be present and functional in UFs [29]. Prolactin strongly activates STAT5 and MAPK signaling in rat and human myometrial cell lines. Moreover, Prolactin produced from UFs may stimulate the transdifferentiation of the myometrium (MM) cells to myofibroblasts, contributing to the fibrotic nature of UFs [29].

2.2. ECM and Growth Factors

The ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. Therefore, a better understanding of ECM composition and metabolism in UFs is critical for developing new therapeutics for UFs. In addition, several growth factors have been shown to trigger the ECM accumulation in UFs, including transforming growth factor-β, activin-A, and platelet-derived growth factor [24].
TGF-β initiates the cascade of signal transduction that elicits biological actions on responding cells via receptors on the plasma membrane. The central mechanism of signal transduction by the TGF-β family receptors follows a well-characterized process of interactions and receptor-mediated phosphorylation. Upon ligand binding and the following cascade steps, the trimeric complex (SMAD2, 3, 4) translocates into the nucleus and associates with high-affinity DNA binding transcription factors and chromatin remodeling proteins, thereby positively or negatively regulating the transcription of the TGF-β-responsive genes [30]. Numerous studies demonstrated that TGF-β signaling plays an important role in the pathogenesis of UFs. Abnormal ECM accumulation and deposition have been shown to be associated with the activation of TGF-β signaling in UFs. Several studies have demonstrated that TGF-β3 stimulates the production and secretion of ECM macromolecules and alters the expression of MMP members [24][31].
Activin-A is a member of the TGF-β superfamily, a large family of over 30 structurally related proteins. Activin A has been recognized as a multifunctional cytokine expressed in a wide range of tissues and cells, and growing evidence implicates activin A in the pathogenesis of UFs. In vitro studies demonstrated that Activin A promoted cell proliferation and increased ECM protein accumulation via p38 MAPK signaling in immortalized UF cells [32][33]. In addition, activin A significantly increased mRNA expression of FN, collagen 1A1, and versican in primary UF cells concomitantly with the activation of Smad-2/3 signaling, but not with changes in ERK and P38 signaling [34].
The platelet-derived growth factor (PDGF) family belongs to the growth factor systems. Its dysregulation is involved in a wide array of pathological conditions, such as fibrosis, neurological disorders, atherosclerosis, and tumorigenesis [35]. The PDGF family consists of four members: PDGF-A, PDGF-B, PDGF-C, and PDGF-D. Members of the PDGF family bind to and signal through the PDGF tyrosine kinase receptors with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Upon ligand binding, the receptor dimerization results in receptor autophosphorylation on tyrosine residues. Autophosphorylation further activates the receptor kinase and docking sites for downstream signaling molecules and the modulation of different pathways [36]. PDGF is upregulated in about 80% of UFs compared to adjacent myometrial tissues [37] and can promote the growth of myometrial and UF-derived smooth muscle cells, which is one of the main cell populations contributing to ECM production and secretion. In addition, PDGF-C prolongs the survival of UF-derived SMCs in Matrigel plugs implemented subcutaneously in immunocompromised mice. Furthermore, PDGF can increase the collagen levels in both myometrial and UF cells [38].

2.3. ECM and Cytokines

Cytokines are small proteins with characteristics of intercellular messengers, which have a complex regulatory influence on inflammation and immunity. In addition, cytokines play an important role in many other biological processes, including tumorigenesis [39]. Proinflammatory cytokines have been shown to cause potent and consistent changes in ECM expression in many cell types [40][41]. Several cytokines have been implicated in the development of UFs [42]. Tumor necrosis factor-α (TNF-α) is a cell-signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. It was reported that TNF-α serum levels in women with clinically symptomatic UFs were significantly higher than in the control group [43]. TNF-a can increase the expression of activin-A, the ECM inducer, in UF and MM cells, suggesting that TNF-a may increase the deposition of ECM, leading to UF pathogenesis [24][44]. Further investigation of TNF-a-induced alterations in ECM production and components will help better understand the cytokine role in the ECM-mediated signal pathway in UFs.

2.4. Cell Types Contributing to ECM Production in Uterine Fibroids

UF heterogeneity exists at many levels, including etiology, clinical symptoms, and pathogenesis, which have significant ramifications for research design and therapeutic decisions [13][45]. The ECM forms a milieu surrounding cells that reciprocally influence cellular function to modulate diverse fundamental aspects of cell biology [46].
Intracellular heterogeneity is present in UFs with multiple cellular compositions [47]. Among them, SMCs and fibroblast populations are dominant in contributing to ECM secretion and participate in the collagen signaling network in the MED12-variant-positive UFs compared to the MM tissues [48]. Accordingly, increased SMC and fibroblast proliferation in UFs is correlated to enhanced ECM accumulation, the characteristic feature of UFs [37][49]. In addition, there was a significant increase in UF cells when cocultured with UF-derived fibroblasts. UF-derived fibroblasts can stimulate the production of collagen type I in the medium cocultured with UF cells [50].

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Subjects: Obstetrics & Gynaecology
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