title: IFNβ impairs extracellular matrix formation leading to inhibition of mineralization by effects in the early stage of human osteoblast differentiation.
abstract: 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.
authors: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: V J
authors: VJ
authors: Woeckel
authors: M
authors: M
authors: Eijken
authors: J
authors: J
authors: van de Peppel
authors: H
authors: H
authors: Chiba
authors: B C J
authors: BC
authors: van der Eerden
authors: J P T M
authors: JP
authors: van Leeuwen
mesh_terms: D002113:Calcification, Physiologic / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism*; D010006:Osteoblasts / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D055153:Stem Cell Niche; D013997:Time Factors
chemical_list: D050835:Interferon Regulatory Factors; D012333:RNA, Messenger; D016899:Interferon-beta