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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.

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.

Interferon-beta (IFN-beta) achieves its beneficial effect on multiple sclerosis (MS) via anti-inflammatory properties. In this study, we assessed the expression of the brain-derived neurotrophic factor (BDNF) in peripheral blood mononuclear cells (PBMC) from relapsing-remitting multiple sclerosis (RRMS) patients treated or not with IFN-beta. Intracellular BDNF was measured by Western blot and ELISA and compared with serum BDNF. We found higher levels of BDNF in PBMC of IFN-beta-treated versus non-treated patients, whereas serum levels of BDNF were similar. We hypothesize that the increased intracellular BDNF secondary to IFN-beta is not released in the periphery. This release is probably not tissue specific but in MS patients, BDNF could be specifically delivered by PBMC at the site of re-activation, i.e. within the central nervous system.

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.

Perivascular leukocyte infiltration into the central nervous system is characteristic of multiple sclerosis (MS) pathology. Interferon-beta (IFN-beta) has shown efficacy in the treatment of patients with MS, but the relevant mechanisms remain incompletely understood. In this study the effects of IFN-beta on leukocyte transendothelial migration were investigated using cells relevant to MS pathogenesis, namely human brain microvascular endothelial cells (HB-MVEC). Activated, but not resting leukocytes exhibited a high transendothelial migration capacity. HB-MVEC prestimulated with tumor necrosis factor (TNF) and IFN-gamma significantly promoted leukocyte transendothelial migration. IFN-beta inhibited the activated leukocyte transendothelial migration on TNF/IFN-gamma-activated HB-MVEC in a dose-dependent manner. A matrix metalloproteinase (MMP) inhibitor and monoclonal antibodies to lymphocyte function antigen-1 (LFA-1) or intercellular adhesion molecule-1 (ICAM-1), but not to very late antigen-4 or to vascular cell adhesion molecule-1 significantly inhibited the transendothelial migration of stimulated leukocytes, suggesting that this phenomenon involves the LFA-1/ICAM-1 interaction and MMP. However IFN-beta did not interfere with the binding of leukocytes to HB-MVEC unless IFN-beta was preincubated with leukocytes or added to HB-MVEC at the time of stimulation. Furthermore IFN-beta did not modulate the expression of adhesion molecules on either stimulated leukocytes or activated HB-MVEC, but partially reduced TNF and interleukin-1 production from stimulated leukocytes during coculture with HB-MVEC. Interestingly, in the presence of IFN-beta, a significant down-regulation of MMP-9 release from stimulated leukocytes was found, especially for the activated form of MMP-9. These results indicate that inhibition of leukocyte transendothelial migration is an important mechanism accounting for the beneficial effects of IFN-beta in the treatment MS patients.