title: Signaling pathway STAT1 is strongly activated by IFN-β in the pathogenesis of osteoporosis.
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.
authors.affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. seeliger@uchir.me.tum.de.
authors.forename: Claudine
authors.initials: C
authors.lastname: Seeliger
authors.affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. lilaschyschka@yahoo.de.
authors.forename: Lilianna
authors.initials: L
authors.lastname: Schyschka
authors.affiliation: Berlin-Brandenburger Centrum für Regenerative Therapien, Julius Wolff Institut, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. zienab.kronbach@charite.de.
authors.forename: Zienab
authors.initials: Z
authors.lastname: Kronbach
authors.affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. angelaw@gmx.at.
authors.forename: Angela
authors.initials: A
authors.lastname: Wottge
authors.affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. vangriensven@uchir.me.tum.de.
authors.forename: Martijn
authors.initials: M
authors.lastname: van Griensven
authors.affiliation: Berlin-Brandenburger Centrum für Regenerative Therapien, Julius Wolff Institut, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. britt.wildemann@charite.de.
authors.forename: Britt
authors.initials: B
authors.lastname: Wildemann
authors.affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. vester@uchir.me.tum.de.
authors.forename: Helen
authors.initials: H
authors.lastname: Vester
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis; D010024:Osteoporosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D016899:Interferon-beta; D016760:Proto-Oncogene Proteins c-fos; D050794:STAT1 Transcription Factor; D048029:TNF Receptor-Associated Factor 6; D000099169:Fos-Related Antigen 1; C494079:STAT1 protein, human