Interferon-β modulates bone-associated cytokines and osteoclast                 precursor activity in multiple sclerosis patients

Weinstock‐Guttman, Bianca; Hong, Junhao; Santos, Roseane Maria Maia; Tamaño‐Blanco, Miriam; Badgett, Darlene; Patrick, Kara; Baier, Monika; Feichter, Joan; Gallagher, Eileen; Garg, Neeta; Ramanathan, Murali

doi:10.1177/1352458506070605

Cited by 34 publications

(23 citation statements)

References 52 publications

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“…BMD values from persons with MS were adjusted for BMI in less than half of the published studies [24,26,30,33,39]. Not unexpectedly, BMD at the femoral neck and lumbar spine are associated with current ambulatory function and possibly physical activity during growth, indicating a major effect of exercise and mechanical loading at these skeletal sites.…”

Section: Discussionmentioning

confidence: 99%

Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis

2009

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The implications of having multiple sclerosis (MS) for bone health are incompletely understood. The aim of this population-based study is to identify past and current exposures that are associated with bone mass in fully ambulatory persons with MS up to age 50 years and to determine the prevalence of low bone mineral density (BMD) in this group. We measured BMD (hips, lumbar spine, forearms), physical function, BMI, and serum 25(OH) vitamin D in 55 women and 25 men with MS. Patients provided information on demographic variables and medical history, as well as past and current vitamin D and calcium intake, physical activity, and lifestyle habits. In regression analyses, BMD levels were adjusted for age, sex, and BMI. At the femoral neck, strong associations were found for walking distance (beta = 0.152; P < 0.001) and age (beta = -0.004; P = 0.003), and less certain associations for male sex (beta = 0.055; P = 0.014) and 10-foot timed tandem walk (-0.008; P = 0.013). At the lumbar spine, walking distance (beta = 0.013; P = 0.006) and possibly physical activity growing up (beta = 0.035; P = 0.028) and male sex (beta = -0.057; P = 0.042), were associated with BMD. At the ultradistal radius, strength of grip (beta = 0.001; P = 0.002), and, less certainly, summer outdoor activities age 16-20 (beta = 0.021; P = 0.009), and age at MS onset (beta = 0.002; P = 0.036) were associated with BMD. Low BMD (z score < or = -2) was present in 19 out of 80 patients. This study shows that MS-related variables as well as past exposures differentially affect BMD at three clinically important skeletal sites. Low BMD is prevalent in these young patients. Bone health should receive attention in care for persons with MS.

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Section: Discussionmentioning

confidence: 99%

Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis

2009

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“…Combinatory medication of IFNa and Ribavirin (in the case of Hepatitis C) is under debate as it affects bone mineral density (Solis-Herruzo et al, 2000;Hofmann et al, 2008). There are also indications that medications including IFNb affect the RANK/RANKL system and may modulate bone phenotypes in MS patients (Weinstock-Guttman et al, 2006). Therefore, an understanding of type I IFN-mediated effects on bone is of great interest to improve medication and circumvent potential bone side effects.…”

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confidence: 98%

IFNβ impairs extracellular matrix formation leading to inhibition of mineralization by effects in the early stage of human osteoblast differentiation

Woeckel

Eijken

Peppel

et al. 2012

Journal Cellular Physiology

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Osteoimmunology is an emerging field of research focused on the interaction of the immune system and bone. In this study we demonstrate that human osteoblasts are sensitive to the immune cytokine interferon (IFN)β. Osteoblasts respond to IFNβ as shown by the induction of several known IFN target genes such as interferon-induced (IFI) proteins (IFIT1, IFI44L), interferon-stimulated gene factor 3 (ISGF3) complex and the induction of IFNβ itself. We demonstrated that IFNβ has severe inhibitory effects on mineralization of osteoblast-derived extracellular matrix (ECM). Analysis of the timing of the IFNβ effects revealed that committed osteoblasts in early stage of differentiation are most sensitive to IFNβ inhibition of mineralization. A single IFNβ treatment was as effective as multiple treatments. During the progress of differentiation osteoblasts become desensitized for IFNβ. This pinpoints to a complex pattern of IFNβ sensitivity in osteoblasts. Focusing on early osteoblasts, we showed that IFNβ decreased gene expression of ECM-related genes, such as type I Collagen (COL1A1), fibronectin (FN1), fibullin (FBLN1), fibrillin (FBN2), and laminin (LAMA1). Additionally, ECM produced by IFNβ-treated osteoblasts contained less collagen protein. IFNβ stimulated gene expression of osteopontin (OPN), annexin2 (ANXA2), and hyaluronan synthase 1 (HAS1), which are important factors in the adhesion of hematopoietic stem cells (HSC) in the HSC niche. In conclusion, IFNβ directly modifies human osteoblast function by inhibiting ECM synthesis eventually resulting in delayed bone formation and mineralization and induces a HSC niche supporting phenotype. These effects are highly dependent on timing of treatment in the early phase of osteoblast differentiation.

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“…Nevertheless, they received continuous IFN-β treatment that may also affect the RANKL/OPG system. In a small cohort of RR-MS patients, it was shown that IFN-β caused an immediate upregulation of serum sRANKL and OPG levels, with a long-term increase in the bone formation marker, osteocalcin [36]. The study by Zhao et al [37] showed that IFN-β administration increased the serum level of OPG and did not affect serum RANKL a week after treatment in rheumatoid arthritis patients.…”

Section: Discussionmentioning

confidence: 96%

“…Weinstock-Guttman et al [36] assessed the dynamic of RANKL and OPG expression in the PBL of RR-MS patients during IFN-β treatment, showing higher induction within 48 h compared to in the control group. Another group of authors compared serum levels of sRANKL and OPG as well as a number of bone markers, in RR-MS patients and controls, showing higher sRANKL and OPG levels in RR-MS [21].…”

Section: Discussionmentioning

confidence: 99%

RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Glasnović

Stojić

Dežmalj

et al. 2018

Neuroimmunomodulation

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Objectives: Our study focused on the RANKL (receptor activator of nuclear factor-κB ligand)/RANK/OPG (osteoprotegerin) axis and selected proinflammatory/immunoregulatory upstream mediators in the peripheral blood (PBL) and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. Methods: PBL and CSF were collected from healthy controls (n = 35) and MS patients at the clinical onset of the disease (n = 33). In addition, PBL samples were obtained from relapse-remitting (RR)-MS patients (n = 30). Patients were assessed by means of the expanded disability status scale (EDSS) and routine laboratory parameters. Soluble (s)RANKL and OPG were measured in the CSF and plasma; gene expression was detected for RANKL, RANK, OPG, and selected cytokines/chemokines (interleukin [IL]-4, IL-10, IL-17, CCL2, and CXCL12) in PBL mononuclear cells. Results: The OPG level in the CSF was lower in MS patients at clinical onset than in controls. Moreover, the sRANKL/OPG ratio was higher in the CSF of MS patients at clinical onset and in the plasma of RR-MS patients than in controls. Gene expression of RANKL/RANK/OPG in PBL mononuclear cells was higher only in RR-MS patients. IL-4, CCL2, and CXCL12 were positively correlated and IL-10 was negatively correlated with RANKL/RANK expression. OPG was negatively correlated with EDSS and alkaline phosphatase level. Conclusion: Our study revealed that changes of RANKL/RANK/OPG axis are associated with MS, particularly the decreased OPG level in the CSF at disease onset. Therefore, these factors may serve as disease biomarkers and molecular targets of novel therapeutic approaches.

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Interferon-β modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients

Abstract: IFN-beta treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.

Cited by 34 publications

References 52 publications

Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis

Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis

IFNβ impairs extracellular matrix formation leading to inhibition of mineralization by effects in the early stage of human osteoblast differentiation

RANKL/RANK/OPG Axis Is Deregulated in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

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