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¹ Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
² Institute of Pharmacology and Toxicology, University of Vienna, A-1090 Vienna, Austria
³ Center of Molecular Medicine of the Austrian Academy of Sciences (CeMM), A-1090 Vienna, Austria
⁴ Ludwig Boltzmann-Institute for Rheumatology, A-1130 Vienna, Austria
⁵ Department of Experimental Trauma Surgery, University School of Hamburg, D-20146 Hamburg, Germany
⁶ Boehringer Ingelheim, A-1121 Vienna, Austria
⁷ Research Institute of Molecular Pathology, A-1030 Vienna, Austria

CORRESPONDENCE Georg Schett: georg.schett{at}meduniwien.ac.at

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.

Abbreviations used: hTNFtg, human TNF-transgenic; MAPK, mitogen-activated protein kinase; micro-CT, microcomputed tomography; MKP, MAPK phosphatase; OPG, osteoprotegerin; RA, rheumatoid arthritis; RANKL, receptor activator of NF-B ligand; TRAP, tartrate-resistant acidic phosphatase.

B. Görtz's present address is Institute of Pathology, University of Giessen, 35390 Giessen, Germany.

K. Skriner's present address is Rheumatology & Clinical Immunology, Charité, D-10117 Berlin, Germany.

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