Signaling pathway STAT1 is strongly activated by IFN-β in the pathogenesis of osteoporosis

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Despite extensive research, the underlying pathological mechanisms of osteoporosis are not completely understood. Recent studies have indicated a distinct role for the IFN-β/STAT1 pathway in bone metabolism. An inhibitory effect of IFN-β on osteoclastogenesis has been detected and STAT1/2 has been shown to influence osteoblastic bone metabolism. So far, no data concerning the IFN-β/STAT1 pathways in osteoblasts and osteoclasts from osteoporotic and non-osteoporotic patients are available. The aim of the study was to analyze these pathways in both cell types.

Methods

Osteoblasts were isolated from the femoral heads of 12 osteoporotic and 11 non-osteoporotic patients and monocytes were differentiated into osteoclasts. After the differentiation period, cells were stimulated once with 20 and 100 ng/mL IFN-β for 4 days. Viability, activity, bone metabolism-related genes, and the proteins Fra1, SOCS1, STAT1, p-STAT1, and TRAF6 were analyzed.

Results

Viability, activity, and gene expressions were not affected by stimulating the osteoblasts. However, in osteoporotic osteoclasts, which display a significantly higher basal osteoclastic activity, the stimulation with IFN-β lead to significant inhibition. Further, an increased STAT1 activation was detected in both cell types with no significant differences between the groups. Regarding the phosphorylation of STAT1, no significant influence was detected in osteoblasts but the IFN-β stimulation led to a significant increase of p-STAT1 in osteoclasts of both groups.

Conclusions

IFN-β is a principal mediator in the pathogenesis of osteoporosis by inhibiting osteoclasts and inducing and activating STAT1. Our results also confirm this in cells from osteoporotic and non-osteoporotic patients. Strong inhibitory effects on the osteoclastogenesis of osteoporotic osteoclasts were detectable. Nevertheless, osteoblast activity was not negatively affected by IFN-β stimulation. These results may contribute to a better understanding of the underlying pathological signaling pathways of osteoporosis.

Electronic supplementary material

The online version of this article (doi:10.1186/s40001-014-0074-4) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 29

Record: found
Abstract: found
Article: not found

Osteoporosis and inflammation.

G D Mundy (2007)

Osteoporosis represents a major healthcare burden, affecting approximately 10 million people aged over 50 years in the United States and with another 30 million or more at risk. One of the major contributing factors to osteoporosis is withdrawal of estrogen during menopause in women. Human and animal experiments have implicated pro-inflammatory cytokines as primary mediators of the accelerated bone loss at menopause including interleukin-1, tumor necrosis factor-alpha, and interleukin-6. Increased production of pro-inflammatory cytokines is associated with osteoclastic bone resorption in a number of disease states including rheumatoid arthritis, periodontitis, and multiple myeloma; estrogen withdrawal is associated with increased production of pro-inflammatory cytokines, and exposure of bone cultures to supernatants from activated leukocytes is associated with increased bone resorption. A major advance has been the discovery of RANKL, its receptor RANK, and the endogenous inhibitor osteoprotegerin. The binding of RANKL to RANK is essential for the differentiation and activation of osteoclasts and mediates the actions of essentially all known stimulators of osteoclastic bone resorption. RANKL expression is heightened in post- compared with pre-menopausal women, and this effect is attenuated by estrogen replacement therapy. RANKL is also a therapeutic target; a human antibody with high specificity and affinity to RANKL is currently under clinical evaluation for the treatment of osteoporosis in post-menopausal women and of metastatic bone disease in cancer patients with bone metastasis. Early data are promising.

0 comments Cited 174 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta.

Tomohiko Suzuki, Koichi Matsuo, Kozo Nakamura … (2002)

Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis. Signalling by RANKL (receptor activator of NF-kappaB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation, and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-beta (IFN-beta) gene in osteoclast precursor cells, and that IFN-beta inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-beta gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates-the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-beta signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-beta system in a new context, and may offer a molecular basis for the treatment of bone diseases.

0 comments Cited 144 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis.

H Takayanagi, H Iizuka, T Juji … (2000)

To clarify the mechanism by which osteoclasts are formed in culture of rheumatoid synoviocytes by exploring the involvement of receptor activator of nuclear factor kappaB ligand (RANKL)/osteoclast differentiation factor (ODF). Osteoclast formation was evaluated in cocultures of rheumatoid synovial fibroblasts and peripheral blood mononuclear cells (PBMC) in the presence of macrophage colony stimulating factor and 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) utilizing separating membrane filters. RANKL/ODF expression was examined by Northern blotting in synovial tissues from 5 rheumatoid arthritis (RA) patients and tissues from patients with giant cell tumor (GCT), osteosarcoma (OS), and osteoarthritis (OA). RANKL/ODF expression and the ability of synovial fibroblasts to support osteoclastogenesis were investigated in coculture with PBMC in the presence or absence of 1,25(OH)2D3, and soluble RANKL/ODF and osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) were measured by enzyme-linked immunosorbent assay. The effects of OPG/OCIF on the osteoclastogenesis in the primary culture of rheumatoid synoviocytes and the coculture system were determined. Synovial fibroblasts did not induce osteoclastogenesis when separately cocultured with PBMC. Northern blotting revealed that RANKL/ODF was highly expressed in all tissues from RA and GCT patients, but not from OA or OS patients. Cultured rheumatoid synovial fibroblasts efficiently induced osteoclastogenesis in the presence of 1,25(OH)2D3, which was accompanied by up-regulated expression of RANKL/ODF and decreased production of OPG/OCIF. Osteoclastogenesis from synoviocytes was dose-dependently inhibited by OPG/OCIF. RANKL/ODF expressed on synovial fibroblasts is involved in rheumatoid bone destruction by inducing osteoclastogenesis and would therefore be a good therapeutic target.

0 comments Cited 119 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Claudine Seeliger: seeliger@uchir.me.tum.de

Lilianna Schyschka: lilaschyschka@yahoo.de

Zienab Kronbach: zienab.kronbach@charite.de

Angela Wottge: angelaw@gmx.at

Martijn van Griensven: vangriensven@uchir.me.tum.de

Britt Wildemann: britt.wildemann@charite.de

Helen Vester: vester@uchir.me.tum.de

Journal

Journal ID (nlm-ta): Eur J Med Res

Journal ID (iso-abbrev): Eur. J. Med. Res

Title: European Journal of Medical Research

Publisher: BioMed Central (London )

ISSN (Print): 0949-2321

ISSN (Electronic): 2047-783X

Publication date (Electronic): 7 January 2015

Publication date PMC-release: 7 January 2015

Publication date Collection: 2015

Volume: 20

Issue: 1

Electronic Location Identifier: 1

Affiliations

[ ]Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675 Munich, Germany

[ ]Berlin-Brandenburger Centrum für Regenerative Therapien, Julius Wolff Institut, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany

Article

Publisher ID: 74

DOI: 10.1186/s40001-014-0074-4

PMC ID: 4300729

PubMed ID: 25563300

SO-VID: 62b8096b-3a5a-4b7e-bb18-7d5282bac213

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 October 2014

Date accepted : 4 December 2014

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: ifn-β,osteoblasts,osteoclasts,osteoporosis,stat1 signaling

Data availability:

ScienceOpen disciplines: Medicine

Keywords: ifn-β, osteoblasts, osteoclasts, osteoporosis, stat1 signaling

Comments

Comment on this article

scite_

Cited by 19

See all cited by

Most referenced authors 863

See all reference authors

Signaling pathway STAT1 is strongly activated by IFN-β in the pathogenesis of osteoporosis

Read this article at

Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Neuronal Signaling

Most cited references 29

Osteoporosis and inflammation.

RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta.

Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 290

Cited by 19

Most referenced authors 863