Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients

Abstract

Endometrial receptivity is mediated by adhesion molecules at the endometrium-trophoblast interface where osteopontin (OPN) and CD44 form a protein complex that plays an important role in embryo recognition. Here, we undertook a prospective study investigating the expression and regulation of OPN and CD44 in 50 fertile and 31 infertile ovulatory polycystic ovarian syndrome (PCOS) patients in the proliferative and secretory phases of the natural menstrual cycle and in 12 infertile anovulatory PCOS patients. Endometrial biopsies and blood samples were evaluated for expression of OPN and CD44 using RT-PCR, immunohistochemistry and ELISA analysis to determine circulating levels of OPN, CD44, TNF-α, IFN-γ and OPN and CD44 levels in biopsy media. Our findings highlighted an increased level of circulating OPN and CD44 in serum from infertile patients that inversely correlated with expression levels in endometrial tissue and positively correlated with levels secreted into biopsy media. OPN and CD44 levels positively correlated to each other in serum and media from fertile and PCOS patients, as well as to circulating TNF-α and IFN-γ. In vitro analysis revealed that hormone treatment induced recruitment of ERα to the OPN and CD44 promoters with a concomitant increase in the expression of these genes. In infertile patients, inflammatory cytokines led to recruitment of NF-κB and STAT1 proteins to the OPN and CD44 promoters, resulting in their overexpression. These observations suggest that the endometrial epithelial OPN-CD44 adhesion complex is deficient in ovulatory PCOS patients and displays an altered stoichiometry in anovulatory patients, which in both cases may perturb apposition. This, together with elevated circulating and local secreted levels of these proteins, may hinder endometrium-trophoblast interactions by saturating OPN and CD44 receptors on the surface of the blastocyst, thereby contributing to the infertility associated with ovulating PCOS patients. Key messages • Endometrial epithelial OPN-CD44 adhesion complex levels are deficient in ovulatory PCOS patients contributing to the endometrial infertility associated with ovulating PCOS patients. • Circulating levels of OPN, CD44 and inflammatory cytokines TNF-α and IFN-γ are altered in infertile PCOS patients. • Increased levels of both OPN and CD44 in biopsy media and serum inversely correlate with endometrial expression of these markers in endometrial tissue. • In infertile PCOS patients, high levels of oestrogens and inflammatory cytokines stimulate the recruitment of transcription factors to the OPN and CD44 promoters to enhance gene transcription. • Our study identifies a novel crosstalk between the CD44-OPN adhesion complex, ERα, STAT1 and NF-κB pathways modulating endometrial receptivity.

Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

“…These genes play important roles in ovarian function and androgen metabolism and are likely to be involved in pathogenesis of PCOS. For example, the deficiency of endometrial epithelial CD44 adhesion complex contributes to the endometrial infertility ( Paravati et al, 2020 ) and likely to be involved in the pathogenesis of PCOS by affecting ovarian function. In conclusion, we constructed the miRNAs regulatory networks of PCOS and identified several important target genes regulated by aberrant miRNAs.…”

Identification of key genes associated with polycystic ovary syndrome (PCOS) and ovarian cancer using an integrated bioinformatics analysis

“…Moreover, RNF144B, JCHAIN, OR7E14P, IL27RA, PTPRD, OGN, CRISPLD2, and GALNT6 have not been confirmed in PCOS progression. STAT1 interacts with the CD44-OPN adhesion complex, ERα, and NF-κB to formulate significant crosstalk, resulting in the modulation of endometrial receptivity [ 41 ]. Insulin enhances STAT1 and STAT3 expression to repress the levels of miR-27a-3p, which could decrease granule cell proliferation and apoptosis escape [ 42 ].…”

Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome

“…These genes play important roles in ovarian function and androgen metabolism, and likely to be involved in pathogenesis of PCOS. For example, the deficiency of endometrial epithelial CD44 adhesion complex contributes to the endometrial infertility [52]，and likely to be involved in the pathogenesis of PCOS by affecting ovarian function. In conclusion, we constructed the miRNAs regulatory networks of PCOS and identified several important target genes regulated by aberrant miRNAs.…”