Spotlight on Proteases: Roles in Ovarian Health and Disease

Abstract

Proteases play crucial roles in ovarian folliculogenesis, regulating several processes from primordial follicle activation to ovulation and corpus luteum formation. This review synthesizes the current knowledge on the diverse functions of proteases in ovarian physiology and pathology. We discuss the classification and regulation of proteases, highlighting their importance in extracellular matrix remodeling, cell signaling, and apoptosis during ovarian follicular development. We explore the roles of several proteases including matrix metalloproteinases, tissue inhibitors of metalloproteinases, the plasminogen activator system, and cathepsins, and their roles in the critical functions of ovarian biology including follicle dynamics and senescence. Furthermore, we address the involvement of proteases in ovarian pathologies, including cancer, polycystic ovary syndrome, and primary ovarian insufficiency. By integrating recent findings from clinical genomics and animal models, this review provides a comprehensive overview of protease functions in the ovary, emphasizing their potential use for therapeutic interventions in reproductive medicine.

Keywords: cathepsins; matrix metalloproteinases; ovarian cancer; ovarian reserve; ovary; polycystic ovary syndrome; primary ovarian insufficiency; proteases.

Figure 1

Mechanisms of protease activation: (A) zymogen activation through proteolytic cleavage triggered by factors including specific proteases, autocatalysis, or cofactor binding; (B) activation of serine proteases featuring the Asp–His–Ser catalytic triad, which facilitates nucleophilic attack on peptide bonds; (C) activation of cysteine proteases where the thiolate group serves as the nucleophile; (D) activation of aspartic proteases involving dual aspartate residues that use water for peptide bond hydrolysis; (E) mechanisms of activation of tissue–type (tPA) and urokinase–type (uPA) plasminogen activators; (F) activation of metalloproteases through the cysteine switch and zinc-mediated catalysis.

Figure 2

Schematic Overview: Ovarian Follicle Development Through Corpus Luteum Formation and Involvement of Various Protease. Proteases regulate critical processes including follicular activation, differentiation, migration, ECM remodeling, and gonadotropin-dependent responses. Several extracellular matrix components (proteoglycans, laminin, and collagen) and cell types (fibroblasts and mesenchymal cells) interact with follicle cells during the developmental process. Proteases are involved in ECM remodeling, which is critical for follicle growth, oocyte maturation, and luteal phase transition.

Figure 3

Roles of proteases in ovarian health and disease. Matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), plasminogen activators (PAs), plasminogen activator inhibitors (PAIs), ADAMTS, cathepsins, and kallikreins are involved in critical physiological processes of the ovary, including folliculogenesis, extracellular matrix (ECM) remodeling, apoptosis, ovulation, corpus luteum (CL) development. The dysregulation of proteases can lead to several pathological conditions including cancer, polycystic ovary syndrome (PCOS), primary ovarian insufficiency (POI), and ovulatory irregularities.