Lysyl oxidase blockade ameliorates anovulation in polycystic ovary syndrome.

Abstract

Is overexpression of lysyl oxidase (LOX), an enzyme responsible for the cross-linking of collagens, a cause of anovulation in polycystic ovary syndrome (PCOS)? LOX overexpression was present in PCOS ovaries, due at least in part to interleukin-1β (IL-1β), and inhibition of LOX activity with β-aminopropionitrile (BAPN) ameliorated polycystic ovary morphology and anovulation. Aberrant ovarian extracellular matrix (ECM) remodeling and inflammation may contribute to the development of PCOS. It remains unknown whether proinflammatory IL-1β is a contributing factor for LOX overexpression in PCOS ovaries and whether inhibition of LOX can improve PCOS conditions. LOX and IL-1β abundance in the granulosa cells and follicular fluid was compared between non-PCOS (n = 30) and PCOS (n = 39) patients. The effect and mechanism of IL-1β on LOX expression was examined in cultured primary human granulosa cells. The improvements in PCOS conditions by LOX inhibition with BAPN was investigated in a dehydroepiandrosterone (DHEA)-induced PCOS rat model. The abundance of LOX and IL-1β was measured with quantitative real-time polymerase chain reaction (qRT-PCR), LOX activity assays and enzyme-linked immunosorbent assays (ELISA), respectively. The effect of IL-1β on LOX expression was examined in the presence or absence of inhibitors for signaling molecules and small interfering RNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were conducted to further identify the responsible transcription factor. The role of LOX in ovulation was investigated in a DHEA-induced PCOS rat model with administration of the LOX inhibitor BAPN. The numbers of retrieved total oocytes and MII oocytes were recorded upon ovarian stimulation. Increased abundance of LOX (P < 0.05) and IL-1β (P < 0.05) was observed in the granulosa cells and follicular fluid in PCOS patients. IL-1β increased LOX expression via activation of ERK1/2 and JNK and subsequent activation of the transcription factor c-Jun. Inhibition of LOX with BAPN ameliorated irregular estrous cyclicity (P < 0.05), polycystic ovary morphology and anovulation (P < 0.05) in PCOS rats, but appeared to be ineffective in the improvement of oocyte quality. N/A. Ovarian tissue-directed specific inhibition of LOX in combination with oocyte quality-improving drugs may be more effective in the treatment of PCOS. Inflammation of the ovary is a contributing factor for the aberrant expression of LOX in the PCOS ovary, and inhibition of LOX together with anti-inflammatory therapy may improve the core features of PCOS. This work was supported by National Key R & D Program of China (2017YFC1001403) and Doctorial Innovation Fund of Shanghai Jiao Tong University School of Medicine (BXJ201718). The authors declare no competing financial interests.