The connective tissue components, collagen types I, III and IV, which surround the ovarian follicles, undergo drastic changes during ovulation. Abnormal collagen synthesis and increased volume and density of ovarian stroma characterise the polycystic ovary syndrome (PCOS). Physiologically, collagen synthesis in ovarian follicles is partly regulated by lysyl oxidase (LOX), which catalyzes the collagen and elastin cross-linking and plays indispensable role in the organization of ovarian extracellular matrix (ECM) during follicular development. We have recently shown accumulation of advanced glycation end products (AGEs), nutritional metabolic products that stimulate ECM production and abnormal collagen cross-linking, in ovarian tissue of patients with PCOS. However, the possible link between LOX and AGEs-induced signaling in collagen assembly and stroma formation remain elusive. The present investigation explores the hypothesis that AGE-mediated signaling affects LOX gene transcription in ovarian tissue from patients with PCOS, in a study approved by the local Ethical Committee. We used immunohistochemistry, Western blotting, RT-PCR and EMSA to demonstrate that there is indeed an increased distribution and co-localization of collagen type IV, LOX and AGE molecules in the PCO tissue compared to control, as well as augmented expression of the AGE signaling mediators/effectors, phospho(p)-ERK, phospho(p)-c-Jun and nuclear factor κB (NF-κB). Moreover, we demonstrate binding of the AGE-induced transcription factors, NF-κB and activator protein-1 (AP-1) on LOX promoter, which directly engages AGEs in LOX gene regulation and possibly accounts for the revealed increase in LOX mRNA and protein levels compared to normal. Our findings imply that metabolic products can modulate gene transcription and thus participate in complex cellular processes, such as the cystogenesis in PCO tissue.
Prague, Czech Republic
24 - 28 Apr 2010
European Society of Endocrinology