Estrogen receptor β-deficient female mice develop a bladder phenotype resembling human interstitial cystitis

Abstract

Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the role of the two estrogen receptors (ER), ER␣ and ER␤, has not been investigated. We found that, in the bladders of WT mice, ER␤ is expressed in the basal cell layer of the urothelium. Bladders of male ER␤ ؊/؊ mice were intact and morphologically indistinguishable from those of their WT littermates. However, in female ER␤ ؊/؊ mice, there was ulceration and atrophy of bladder urothelium concomitant with infiltration of ␥␦ T cells concentrated in the areas of atrophy and shedding of urothelium. The data support the idea that activated ␥␦ T cells are causing the damage to the urothelium. The hyperactivity of T cells may be because of an imbalance between ER␣ and ER␤ signaling in female ER␤ ؊/؊ mice. Our data suggest that reduced ER␤ signaling might have a role in the pathogenesis of interstitial cystitis, and ER␤ could be a candidate for a target of medical therapy.␥␦ T cells ͉ urothelium ͉ painful bladder syndrome T he etiology of interstitial cystitis (IC) is unknown, and available treatment options are limited and mostly palliative. There is a clear role for the immune system in this disease: increased numbers of T lymphocytes, particularly ␥␦ T cells, abnormal urothelial HLA, and overexpression of HLA class II (1) in the urothelium and lamina propria in patients with IC strongly suggest a role for autoimmunity in development of IC (2). Because IC is almost exclusively a disease of young women, and symptoms tend to worsen premenopausally or during ovulation, the role of estrogen receptors (ERs) is likely to be important.The bladder is one of those tissues that were long thought to be nonestrogen-responsive on the basis of the lack of ER␣ expression. The discovery of the second ER, ER␤, provided an explanation for the effects of estrogen in several ER␣-negative tissues such as the prostate, intestine, and lung, where ER␤ serves as a modulator of terminal differentiation of epithelium (3-7). ER␤ and ER␣ knockout mice (ER␤ Ϫ/Ϫ and ER␣ Ϫ/Ϫ ) have been invaluable in analyzing and dissecting the functions of ER␤ and ER␣ (8, 9).The predominant ER in the bladder is ER␤, with very little ER␣ expression (10, 11). Reduced ER␤ expression levels have been reported in the bladders of rats with chemically induced cystitis (12). In the present study, with the use of ER␤ Ϫ/Ϫ mice, we have investigated the role of ER␤ in the bladder urothelium. We report that, in female ER␤ Ϫ/Ϫ but not in ER␣ Ϫ/Ϫ mice, there is autoimmune destruction of urothelium resembling IC. ResultsImmunohistochemical staining of WT mouse bladder sections showed that ER␤ is expressed in bladder urothelium and localized in the basal cell layer (Fig. 1). In the bladders of female ER␤ Ϫ/Ϫ mice, there were specific morphol...

Urothelial Signaling

“…For example, ER␤ (female) null mice exhibit urinary bladder alterations that have also been associated with BPS/IC in humans (143). There is also a naturally occurring disease in cats termed feline interstitial cystitis (FIC), which shares nearly all the characteristics of the nonulcerative form of BPS/IC found in humans (53,295).…”

Sterility and absence of histopathological defects in nonreproductive organs of a mouse ERβ-null mutant

“…In contrast, the bladder of females and colon of both sexes of young ER␤KO KI have been reported to display defects that correct with aging (24,25). More specifically, in young female ER␤KO KI mice, the bladder was reported to develop features resembling human interstitial cystitis in females (25) and, in both sexes, the colon exhibited severe subepithelial lymphoid infiltrates predominantly in its proximal portion and an abnormal mucin distribution in its distal portion (24). We conclude that the bladder and colon of our ER␤ ST LϪ/LϪ mutants lack the morphological abnormalities that were found in young ER␤KO KI mutants.…”

“…To eliminate any possible phenotypic effect of these transcript variants, we decided to generate an ER␤-null mutant, hereafter referred to as ER␤ ST LϪ/LϪ , in which exon 3 was deleted through Cre/LoxP-mediated excision and which was devoid of any transcript downstream of exon 3. We report here the characterization of these ER␤ ST LϪ/LϪ mutants, which do not display morphological defects in the prostate, in contrast to ER␤KO CH and ER␤KO KI mutants (13,16,19), or, in contrast to ER␤KO KI mutants, defects in the brain (17), lymphoid tissues (20), heart (21), lung (22,23), colon (24), and urinary bladder (25).…”

Effect of local estrogen therapy (LET) on urinary and sexual symptoms in premenopausal women with interstitial cystitis/bladder pain syndrome (IC/BPS)

“…Indeed, in the bladder of rats with chemically induced cystitis, a significant reduction of estrogen receptor b (ERb) has been found [7]. Moreover, female ERb null mice exhibit urinary bladder alterations that resemble those associated with IC/BPS in humans [8], whereas Cabral et al showed that estrogen deficiency may also lead to bladder wall stiffness, by decreasing some components of the extracellular matrix in female rat urothelial surface [9].…”