title: Acute phase serum amyloid A induces proinflammatory cytokines and mineralization via toll-like receptor 4 in mesenchymal stem cells.
abstract: The role of serum amyloid A (SAA) proteins, which are ligands for toll-like receptors, was analyzed in human bone marrow-derived mesenchymal stem cells (hMSCs) and their osteogenic offspring with a focus on senescence, differentiation and mineralization. In vitro aged hMSC developed a senescence-associated secretory phenotype (SASP), resulting in enhanced SAA1/2, TLR2/4 and proinflammatory cytokine (IL6, IL8, IL1β, CXCL1, CXCL2) expression before entering replicative senescence. Recombinant human SAA1 (rhSAA1) induced SASP-related genes and proteins in MSC, which could be abolished by cotreatment with the TLR4-inhibitor CLI-095. The same pattern of SASP-resembling genes was stimulated upon induction of osteogenic differentiation, which is accompanied by autocrine SAA1/2 expression. In this context additional rhSAA1 enhanced the SASP-like phenotype, accelerated the proinflammatory phase of osteogenic differentiation and enhanced mineralization. Autocrine/paracrine and rhSAA1 via TLR4 stimulate a proinflammatory phenotype that is both part of the early phase of osteogenic differentiation and the development of senescence. This signaling cascade is tightly involved in bone formation and mineralization, but may also propagate pathological extraosseous calcification conditions such as calcifying inflammation and atherosclerosis.
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany. Electronic address: r-ebert.klh@uni-wuerzburg.de.
authors.forename: Regina
authors.initials: R
authors.lastname: Ebert
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany.
authors.forename: Peggy
authors.initials: P
authors.lastname: Benisch
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Krug
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zeck
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Meißner-Weigl
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Steinert
authors.affiliation: Division of Endocrinology, Diabetes Bone Metabolism, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rauner
authors.affiliation: Division of Endocrinology, Diabetes Bone Metabolism, Technical University of Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Hofbauer
authors.affiliation: Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Brettreichstrasse 11, 97074 Würzburg, Germany. Electronic address: f-jakob.klh@uni-wuerzburg.de.
authors.forename: Franz
authors.initials: F
authors.lastname: Jakob
mesh_terms: D000210:Acute-Phase Reaction / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051153:Wnt Proteins
keywords: Inflammation; Mesenchymal stem cells; Mineralization; Osteogenic differentiation; Serum amyloid A; Toll-like receptor