17β-Estradiol Antagonizes Effects of 1α,25-Dihydroxyvitamin D3 on Interleukin-6 Production and Osteoclast-Like Cell Formation in Mouse Bone Marrow Primary Cultures*

Schiller, C; Gruber, Reinhard; Redlich, Kurt; Ho, Guan-Min; Katzgraber, F.; Willheim, Martin; Pietschmann, Péter; Peterlik, Meinrad

doi:10.1210/endo.138.11.5523

Cited by 40 publications

(7 citation statements)

References 20 publications

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“…IL-6-deficient mice have no obvious bone phenotype, but they are protected from bone loss caused by estrogen depletion (27). In bone marrow cultures from ovariectomized mice, the increased osteoclast formation could be prevented by 17␤-estradiol or by a neutralizing IL-6-antibody (28,29). It was also reported that IL-6 stimulates RANKL expression in osteoblasts (30), which induces osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

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Elevated homocysteine (Hcys) serum levels represent a risk factor for several chronic pathologies, including cardiovascular disease, atherosclerosis, and chronic renal failure, and affect bone development, quality, and homeostasis. Hcys influences the formation of a stable bone matrix directly through the inhibition of the collagen cross-linking enzyme lysyl oxidase (Lox) and, as we have shown recently, by repressing its mRNA expression. The aim of this study was to investigate the mechanisms involved in this process. Epidemiological studies have shown that high homocysteine (Hcys) 2 serum levels represent a risk factor for several chronic disorders such as cardiovascular disease, atherosclerosis, chronic renal failure, diabetes, or the metabolic syndrome (1, 2). Moreover, hyperhomocysteinemia is known to affect bone development and homeostasis (3-6). Hcys has been shown to interfere with post-translational modifications of collagen directly by inhibiting lysyl oxidase (Lox) (7) and indirectly by down-regulation of its mRNA expression and of other genes involved in collagen cross-linking. Enzymatic inhibition or mRNA down-regulation of Lox results in changes in collagen cross-linking pattern in vitro (8 -10) and in vivo resulting in decreased bone quality (11)(12)(13). In this context, we have recently reported a correlation between plasma Hcys levels and a collagen cross-link ratio in forming trabecular surfaces in human bone (14).Lysyl oxidase was also identified as a phenotypic suppressor of the ras oncogene in H-ras-transformed NIH3T3 fibroblasts. In this transformed cell line, H-ras participates in an elaborate pathway attenuating the expression of Lox and of many other genes by CpG methylation on DNA. These genes are reactivated by treatment with azacytidine, an inhibitor of DNA (cytosine-5)-methyltransferases. Methylation of cytosine-guanine dinucleotides (CpGs) on DNA is an important epigenetic mechanism involved in the selective regulation of gene expression and in the stabilization of chromatin, thus controlling tissue development and pathogenesis. Aberrant CpG methylation of specific genes is often found in many tumors and tumorigenic cell lines (15).Besides its role as inhibitor of collagen cross-linking, Hcys is also known to play a role in epigenetic gene regulation being directly involved in the DNA methylation process. Hcys represents a methyl group carrier involved in the S-adenosylmethionine-S-adenosylhomocysteine methylation cycle. Here, Hcys is remethylated to methionine, which is further activated to S-adenosylmethionine, the methyl donor in DNA methylation. S-Adenosylmethionine converts to S-adenosylhomocysteine after DNA methylation. Hydrolysis of S-adenosylhomocysteine to homocysteine completes the cycle (16).

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Section: Discussionmentioning

confidence: 99%

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Thaler

Agsten

Spitzer

et al. 2011

Journal of Biological Chemistry

107

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“…6). In mice it is reported that estrogen regulates osteoclast formation via c‐jun expression and c‐jun N‐terminal kinase phosphorylation [Shevde et al, 2000; Srivastava et al, 2001]. This may represent mainly a species difference; human osteoclasts have been reported to lack significant ERs [Collier et al, 1998].…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor‐β modulates synthesis of bone matrix proteins in human osteoblast‐like MG63 cells

Cao

Oakley

et al. 2003

J of Cellular Biochemistry

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Estrogens have complex effects on the skeleton, including regulation of modeling and maintenance of bone mass, which vary with cell type and developmental stage. Osteoblasts are key regulators of skeletal matrix synthesis and degradation. However, whether osteocytes, osteoblasts or earlier progenitors mediate estrogen effects, and the importance of estrogen receptors (ERs) alpha and beta, remain unclear. To address estrogen response in human cells closely related to secretory osteoblasts, we studied MG63 cells with ERalpha or ERbeta reduced to low levels by stable transfection of antisense plasmids. Collagen and alkaline phosphatase expression increased with estrogen in wild-type and ERalpha-suppressed cells, but not in ERbeta-suppressed cells. Matrix secretion occurs as osteoblasts cease dividing, and, in keeping with this, cell proliferation was reduced by estrogen except in ERbeta-antisense cells. No effects of estrogen on wild type or ER-suppressed cells were seen in expression of BMP 2, the BMP antagonist noggin, or Indian hedgehog, products that regulate differentiation of osteoblasts. In contrast to expectations that estrogen would modulate bone degradation, RANKL, CSF-1, and osteoprotegerin did not respond measurably to estrogen, regardless of ER status. In keeping with this result, estrogen response was not observed in assays of osteoclast development from CD14 cells supported by wild-type or ER-silenced MG63 cells. Since estrogens are major regulators of bone degradation in vivo, estrogen effects on osteoclasts may depend on interaction with stimuli present in bone but absent in the model studied. cDNA hybridization showed that additional estrogen-binding proteins including ERRalpha and BCAR3 were expressed by MG63, but estrogen effects in ERbeta-silenced cells were small, so these proteins are either minor regulators in MG63 cells, or act in concert with stimuli in addition to estrogen. We conclude that, in the MG63 cell line, estrogen increases synthesis of matrix proteins via ERbeta, and that, in the absence of additional stimuli, these cells are not major mediators of estrogen effects on osteoclast differentiation. Further, ERalpha is probably much more important in earlier stages of skeletal development, such as growth plate response, than in osteoblasts.

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“…Especially the expression of an estrogen receptor on osteoclasts and its direct activation is still a matter of debate. In previous works we have demonstrated that 17β-estradiol inhibits the generation of osteoclasts in murine bone marrow cultures in a dose-dependent manner diff erent to the biphasic inhibition of SERMs [5]. We could also show that estrogen receptors are expressed by stromal cells and that the mode of action involves IL-6.…”

Section: Discussionmentioning

confidence: 53%

“…Th e protective eff ect of estrogens on bone tissue is assumed to be mostly due to an antiresorptive action [4]. In previous works we have demonstrated that 17β-estradiol can inhibit the generation of osteoclast-like cells in murine bone marrow cultures [5]. Nevertheless, long-term ERT has been associated with increased risk of cancer in estrogen target tissues, in particular breast cancer [6,7].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms involved in the inhibition of osteoclast generation by the benzothiophene SERM LY117018

Wutzl

Gruber

Brozek

et al. 2010

Wien Klin Wochenschr

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Selective estrogen receptor modulators are compounds that act via estrogen receptors in different tissues to mediate either estrogenic or estrogen antagonistic effects in osteoporosis patients. The aim of this study was to assess the effect of the selective estrogen receptor modulator LY117018, a raloxifene analogue, on osteoclastogenesis in vitro. In primary murine bone marrow cultures osteoclasts, defined as TRAP-positive multinucleated cells, were induced by 10(-8) M 1,25-dihydroxyvitamin D(3). LY117018 at concentrations between 10(-12) M and 10(-9) M significantly reduced the number of osteoclasts. At higher concentrations no effect of LY117018 on osteoclast generation was observed. LY117018 enhanced alkaline phosphatase activity of mouse calvaria osteoblasts at a concentration of 10(-14) to 10(-7) M, but had no influence on the proliferation and transcription of RANKL and osteoprotegerin. In order to study the effect of the compound on the production of cytokines that can stimulate bone resorption, spleen cells were incubated with LY117018. Data from four-color flow cytometric analysis indicate a significantly decreased frequency of tumor necrosis factor-α positive CD8(+) cells after treatment with LY117018. These findings suggest that LY117018 can significantly inhibit the generation of osteoclasts and stimulate osteogenic differentiation in vitro. Suppression of tumor necrosis factor-α production by LY117018 may contribute to its anti-osteoclastogenic effect.

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17β-Estradiol Antagonizes Effects of 1α,25-Dihydroxyvitamin D3 on Interleukin-6 Production and Osteoclast-Like Cell Formation in Mouse Bone Marrow Primary Cultures*

Cited by 40 publications

References 20 publications

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Homocysteine Suppresses the Expression of the Collagen Cross-linker Lysyl Oxidase Involving IL-6, Fli1, and Epigenetic DNA Methylation

Estrogen receptor‐β modulates synthesis of bone matrix proteins in human osteoblast‐like MG63 cells

Mechanisms involved in the inhibition of osteoclast generation by the benzothiophene SERM LY117018

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