title: CD44 is a determinant of inflammatory bone loss.
abstract: Chronic inflammation is a major trigger of local and systemic bone loss. Disintegration of cell-matrix interaction is a prerequisite for the invasion of inflammatory tissue into bone. CD44 is a type I transmembrane glycoprotein that connects a variety of extracellular matrix proteins to the cell surface. Tumor necrosis factor (TNF) is a major inducer of chronic inflammation and its overexpression leads to chronic inflammatory arthritis. By generating CD44(-/-) human TNF-transgenic (hTNFtg) mice, we show that destruction of joints and progressive crippling is far more severe in hTNFtg mice lacking CD44, which also develop severe generalized osteopenia. Mutant mice exhibit an increased bone resorption due to enhanced number, size, and resorptive capacity of osteoclasts, whereas bone formation and osteoblast differentiation are not affected. Responsiveness of CD44-deficient osteoclasts toward TNF is enhanced and associated with increased activation of the p38 mitogen-activated protein kinase. These data identify CD44 as a critical inhibitor of TNF-driven joint destruction and inflammatory bone loss.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.forename: Birgit
authors.initials: B
authors.lastname: Görtz
authors.forename: Erika
authors.initials: E
authors.lastname: Reiter
authors.forename: Makiyeh
authors.initials: M
authors.lastname: Tohidast-Akrad
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Oskar
authors.initials: O
authors.lastname: Hoffmann
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Karl
authors.initials: K
authors.lastname: Skriner
authors.forename: Frank
authors.initials: F
authors.lastname: Hilberg
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D010014:Osteolysis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018960:Hyaluronan Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases