Regulation of Extracellular Matrix Remodeling Associated With Pelvic Organ Prolapse

Pelvic organ prolapse (POP), like stress urinary incontinence, has a significant impact on women's quality of life. POP results from a defect of the uterosacral/cardinal ligament complex, anterior vaginal wall, and other supportive tissues. However, there is a paucity of information about the etiology and pathophysiology of POP because of its multifactorial and heterogeneous risk factors. Recent reports of women with POP identified changes in the status of the connective tissue, of which the extracellular matrix (ECM) comprises the major component. Accelerated remodeling in patients with POP is caused by biochemical changes of the ECM, e.g., collagen, elastin, and stromal cells. Myofibroblasts play a role in ECM remodeling and can be modulated by matricellular regulators, e.g., transformation growth factor (TGF)-β, thrombospondin (TSP)-1, and matrix metalloproteases (MMPs). The homeostasis of MMPs with the lysyl oxidase family and fibulin ensure ECM integrity. Disturbances in the balance between synthesis/assembly and degradation of ECM proteins in the pelvic floor may result in POP. The high recurrence rate after pelvic reconstructive surgery necessitates the use of an adjuvant synthetic mesh. With the establishment of an in vitro model, our study showed that the interplay among the ECM, myofibroblasts, and a synthetic mesh can determine the usefulness of the synthetic mesh in pelvic reconstructive surgery. It was hypothesized that accelerated remodeling in patients with POP is caused by biochemical changes in ECM proteins, myofibroblasts, and their regulators. Further studies are needed to elucidate the following issues: first, whether women with POP have abnormal synthesis and/or degradation of the ECM, and different amounts of stromal cells (myofibroblasts); second, whether myofibroblasts exhibit different ECM protein productions under the regulation of MMP, TSP-1, and TGF-β; and third, whether ECM matricellular proteins, e.g., TSP-1 and TGF-β, can modulate the biologic responses of host stromal cells to a synthetic mesh used in pelvic reconstructive surgery. This will be very informative for the further advancement of our understanding and treatment of pelvic floor reconstruction.