CD44 is a determinant of inflammatory bone loss.
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.
Hayer
Silvia
S
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
Steiner
Günter
G
Görtz
Birgit
B
Reiter
Erika
E
Tohidast-Akrad
Makiyeh
M
Amling
Michael
M
Hoffmann
Oskar
O
Redlich
Kurt
K
Zwerina
Jochen
J
Skriner
Karl
K
Hilberg
Frank
F
Wagner
Erwin F
EF
Smolen
Josef S
JS
Schett
Georg
G
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
D018960:Hyaluronan Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases