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

Seeliger C, Schyschka L, Kronbach Z, Wottge A, van Griensven M, Wildemann B, Vester H - Eur. J. Med. Res. (2015)

Bottom Line: Further, an increased STAT1 activation was detected in both cell types with no significant differences between the groups.Our results also confirm this in cells from osteoporotic and non-osteoporotic patients.Strong inhibitory effects on the osteoclastogenesis of osteoporotic osteoclasts were detectable.

View Article: PubMed Central - PubMed

Affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. seeliger@uchir.me.tum.de.

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.

No MeSH data available.


Related in: MedlinePlus

Influence of IFN-β on the activity of osteoblasts and osteoclasts.(a) IFN-β did not influence the AP activity of osteoblasts from osteoporotic and non-osteoporotic patients. (b) Osteoclasts of osteoporotic patients show a significantly increased TRAP-activity reducible by the stimulation with 100 ng/mL IFN-β. Bars represent mean ± sem, n = 12 osteoporosis group, n = 11 non-osteoporosis group. *** P <0.001 compared to the non-osteoporosis group, ° P <0.05, °° P <0.01, °°° P <0.001 compared to untreated cells.
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Fig1: Influence of IFN-β on the activity of osteoblasts and osteoclasts.(a) IFN-β did not influence the AP activity of osteoblasts from osteoporotic and non-osteoporotic patients. (b) Osteoclasts of osteoporotic patients show a significantly increased TRAP-activity reducible by the stimulation with 100 ng/mL IFN-β. Bars represent mean ± sem, n = 12 osteoporosis group, n = 11 non-osteoporosis group. *** P <0.001 compared to the non-osteoporosis group, ° P <0.05, °° P <0.01, °°° P <0.001 compared to untreated cells.

Mentions: Viability of osteoblasts was not influenced by stimulation with IFN-β (Additional file 1: Figure S1). Moreover, the AP activity of osteoblasts from non-osteoporotic and osteoporotic patients was not affected by IFN-β stimulation (Figure 1a).Figure 1


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

Seeliger C, Schyschka L, Kronbach Z, Wottge A, van Griensven M, Wildemann B, Vester H - Eur. J. Med. Res. (2015)

Influence of IFN-β on the activity of osteoblasts and osteoclasts.(a) IFN-β did not influence the AP activity of osteoblasts from osteoporotic and non-osteoporotic patients. (b) Osteoclasts of osteoporotic patients show a significantly increased TRAP-activity reducible by the stimulation with 100 ng/mL IFN-β. Bars represent mean ± sem, n = 12 osteoporosis group, n = 11 non-osteoporosis group. *** P <0.001 compared to the non-osteoporosis group, ° P <0.05, °° P <0.01, °°° P <0.001 compared to untreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4300729&req=5

Fig1: Influence of IFN-β on the activity of osteoblasts and osteoclasts.(a) IFN-β did not influence the AP activity of osteoblasts from osteoporotic and non-osteoporotic patients. (b) Osteoclasts of osteoporotic patients show a significantly increased TRAP-activity reducible by the stimulation with 100 ng/mL IFN-β. Bars represent mean ± sem, n = 12 osteoporosis group, n = 11 non-osteoporosis group. *** P <0.001 compared to the non-osteoporosis group, ° P <0.05, °° P <0.01, °°° P <0.001 compared to untreated cells.
Mentions: Viability of osteoblasts was not influenced by stimulation with IFN-β (Additional file 1: Figure S1). Moreover, the AP activity of osteoblasts from non-osteoporotic and osteoporotic patients was not affected by IFN-β stimulation (Figure 1a).Figure 1

Bottom Line: Further, an increased STAT1 activation was detected in both cell types with no significant differences between the groups.Our results also confirm this in cells from osteoporotic and non-osteoporotic patients.Strong inhibitory effects on the osteoclastogenesis of osteoporotic osteoclasts were detectable.

View Article: PubMed Central - PubMed

Affiliation: Department of experimental Trauma Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany. seeliger@uchir.me.tum.de.

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.

No MeSH data available.


Related in: MedlinePlus