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Estrogen-related receptor ? causes osteoarthritis by upregulating extracellular matrix-degrading enzymes.

ABSTRACT: The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERR?, ERR?, and ERR?, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERR? is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERR? in mouse knee joint or transgenic expression of ERR? in cartilage leads to OA. ERR? overexpression in chondrocytes directly upregulates matrix metalloproteinase (MMP)-3 and MMP13, which are known to play crucial roles in cartilage destruction in OA. In contrast, genetic ablation of Esrrg or shRNA-mediated downregulation of Esrrg in joint tissues abrogates experimental OA in mice. Our results collectively indicate that ERR? is a novel catabolic regulator of OA pathogenesis.

SUBMITTER: Son YO

PROVIDER: S-EPMC5732273 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Estrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes.

Son Young-Ok YO Park Seulki S Kwak Ji-Sun JS Won Yoonkyung Y Choi Wan-Su WS Rhee Jinseol J Chun Churl-Hong CH Ryu Je-Hwang JH Kim Don-Kyu DK Choi Hueng-Sik HS Chun Jang-Soo JS

Nature communications 20171215 1

The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRα, ERRβ, and ERRγ, which are known to regulate various isoform-specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERRγ is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERRγ in mouse knee joint ...[more]

PMID: 29247173

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Project description:BACKGROUND: Extracellular matrix metalloproteinase inducer (EMMPRIN) regulates several biological functions involving the modulation of cell behaviors via cell-cell and cell-matrix interactions. According to its diverse functions, we hypothesized that EMMPRIN may play an important role in endometrial remodeling and establishment of pregnancy in cow. METHODS: In this study, endometrial tissues from the cyclic cows during before ovulation, after ovulation and middle of estrous cycle; and pregnant endometrial tissues from Day 19 to 35 of gestation have been used. Expression of mRNA was analyzed by RT-PCR, qPCR and in situ hybridization whereas protein expression by immunohistochemistry and western blot analysis. RESULTS: EMMPRIN mRNA was expressed in both cyclic and pregnant endometrium and significantly higher in the endometrium at Day 35 of gestation than the cyclic endometrium. In Western blot analysis, an approximately 65 kDa band was detected in the endometrium, and approximately 51 kDa in the cultured bovine epithelial cells and BT-1 cells, respectively. Both in situ hybridization and immunohistochemistry data showed that EMMPRIN was primarily expressed in luminal and glandular epithelium with strong staining on Day 19 conceptus. At Day 19 of gestation, expression of EMMPRIN mRNA on luminal epithelium was decreased than that observed at middle of estrous cycle, however, on Day 30 of gestation, slightly increased expression was found at the site of placentation. Expression of matrix metalloproteinase-2 (MMP-2) and MMP-14 mRNA were mainly detected in stroma and their expression also decreased at Day 19 of gestation however it was also expressed at the site of placentation at Day 30 of gestation as observed for EMMPRIN. Expression of MMP-1 or -9 mRNA was very low and was below the detection limit in the cyclic and pregnant endometrium. CONCLUSION: EMMPRIN from the luminal epithelium may regulate the expression of stromal MMP-2 and -14 suggesting its crucial role in adhesion and fusion of embryo to luminal epithelium by directly itself through physiological tissues remodeling and developmental process, and/or stimulating MMPs to compensate endometrial functions.

Project description:Within the ovary, Estrogen Receptor ? (ER?) is localized to the granulosa cells of growing follicles. 17?-estradiol (E2) acting via ER? augments the actions of follicle stimulating hormone in granulosa cells, leading to granulosa cell differentiation and formation of a preovulatory follicle. Adult ER?-null females are subfertile and possess ovaries with reduced numbers of growing follicles and corpora lutea. Because the majority of E2 production by granulosa cells occurs once puberty is reached, a role for ER? in the ovary prior to puberty has not been well examined. We now provide evidence that lack of ER? disrupts gene expression as early as post-natal day (PND) 13, and in particular, we identify a number of genes of the extracellular matrix (ECM) that are significantly higher in ER?-null follicles than in wildtype (WT) follicles. Considerable changes occur to the ECM occur during normal folliculogenesis to allow for the dramatic growth, cellular differentiation, and reorganization of the follicle from the primary to preovulatory stage. Using quantitative PCR and immunofluorescence, we now show that several ECM genes are aberrantly overexpressed in ER?-null follicles. We find that Collagen11a1, a protein highly expressed in cartilage, is significantly higher in ER?-null follicles than WT follicles as early as PND 13, and this heightened expression continues through PND 23-29 into adulthood. Similarly, Nidogen 2, a highly conserved basement membrane glycoprotein, is elevated in ER?-null follicles at PND 13 into adulthood, and is elevated specifically in the ER?-null focimatrix, a basal lamina-like matrix located between granulosa cells. Focimatrix laminin and Collagen IV expression were also higher in ER?-null ovaries than in WT ovaries at various ages. Our findings suggest two novel observations: a) that ER? regulates granulosa cell gene expression ovary prior to puberty, and b) that ER? regulates expression of ECM components in the mouse ovary.

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Estrogen-related receptor ? causes osteoarthritis by upregulating extracellular matrix-degrading enzymes.

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Estrogen-related receptor γ causes osteoarthritis by upregulating extracellular matrix-degrading enzymes.

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