FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

Abstract

FKBP4 (FKBP52) and FKBP5 (FKBP51) are progestin receptor (PR) co-chaperone proteins that enhance and inhibit, respectively, progestin-mediated transcription by PR. Here, we examined FKBP4 and FKBP5 expression in the eutopic endometrium of fertile women with endometriosis and effects of FKBP4 and FKBP5 on the decidualization of human endometrial stromal cells (HESCs), and assessed HOXA10 regulation of FKBP4. Expression of FKBP4 mRNA was increased in the late proliferative phase and remained elevated throughout the secretory phase. FKBP5 expression was low and remained constant throughout the menstrual cycle. Compared with controls, FKBP4 mRNA expression was decreased in the endometrium of women with endometriosis, whereas no significant endometriosis-related change was seen for FKBP5. Cultured HESCs were treated with either FKBP4 or FKBP5 siRNA and then decidualized by incubation with progesterone (P 4 ) and 8-bromoadenosine cAMP. Treatment of HESCs with FKBP4 siRNA resulted in 60% lower IGFBP1 expression. In contrast, incubation with FKBP5 siRNA did not significantly decrease IGFBP1 expression during in vitro decidualization. HOXA10 and FKBP4 expression increased in parallel during in vitro decidualization. In HESCs, overexpressed HOXA10 enhanced FKBP4 mRNA and protein levels, whereas HOXA10 knockdown decreased FKBP4 mRNA and protein levels compared with controls. Similarly, during in vitro decidualization, FKBP4 expression was decreased in HOXA10-silenced cells. Enhanced HOXA10 expression in HESCs elicits a decidualization mediating increase in FKBP4 expression. The findings are consistent with the observation that women with endometriosis have diminished FKBP4 expression leading to impaired decidualization and infertility. The P 4 resistance seen in endometriosis may be mediated through HOXA10-regulated FKBP4 expression.

Drospirenone induces decidualization in human eutopic endometrial stromal cells and reduces DNA synthesis of human endometriotic stromal cells

“…* P<.05 versus without RU486. (24,25). In addition, decidualization was greater when EuSC were treated with drospirenone and E 2 than with drospirenone alone, which suggests that the expression of P receptors was up-regulated by E 2 (26,27) and that the P receptor agonistic effect of drospirenone may be enhanced.…”

Minireview: Steroid-Regulated Paracrine Mechanisms Controlling Implantation

“…This impaired E metabolism, coupled with the abnormal high expression of P450 aromatase that is seen in endometriotic tissue, leads to excessive local E signaling, which presumably drives the growth of endometriotic lesions. Additional studies have linked impaired expression of other key P-regulated pathways in the stroma to the pathogenesis of endometriosis (105)(106)(107). Bulun's group has also reported that the level of ESR2 expression is significantly greater in endometriotic stroma vs normal (108).…”

The role of Lipoxin A4 in endometrial biology and endometriosis

“…FKBP52 has been shown to be decreased in endometriosis. 167,168 This PR chaperone protein is required for proper progesterone-mediated actions and its reduction in this disease may be a major determinant in progesterone resistance. 136 …”