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The -Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss¹

Christina Böhm,^* Silvia Hayer, Anita Kilian,^* Mario M. Zaiss,^* Susann Finger,^* Andreas Hess, Klaus Engelke, George Kollias,^¶ Gerhard Krönke,^* Jochen Zwerina,^* Georg Schett,^* and Jean-Pierre David^2*

^*Department of Internal Medicine 3, Rheumatology and Immunology, Institute of Experimental and Clinical Pharmacology and Toxicology, and Institute of Medical Physics, University of Erlangen-Nuremberg, Erlangen, Germany; Department of Internal Medicine 3, Medical University of Vienna, Vienna, Austria; and ^¶Institute of Immunology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece

Pharmacological inhibitors have provided evidence for the key role of p38 MAPK in osteoclast differentiation and in inflammation-induced bone loss. However, these inhibitors block more than one of the four p38 isoforms, usually p38 and p38β, and sometimes also other kinases such as JNK3. We show in this study that p38 is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38 as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38 were protected against TNF--induced bone destruction at the site of inflammation as well as against TNF--mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1β expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38-deficient cells, knockdown of p38 in monocytes resulted in a decreased osteoclast differentiation in vitro. It was not caused by major changes in RANKL-mediated ERK or JNK activation but rather associated to an increased NF-B activation caused by a decrease in IB recovery. Thus, our data show that developing specific inhibitors of the -isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by the Deutsche Forschungsgemeinschaft (DFG) Interdisziplinäres Zentrum für Klinische Forschung Erlangen (to C.B.), by the Grant 643 Sonderforschungsbereich of the DFG (to J.-P.D.), and by the PhD Training Grant GK592 from the DFG (to M.M.Z.). This work is also supported by Grant 661 from the Interdisziplinäres Zentrum für Klinische Forschung Erlangen and the Forschergruppe of the DFG, by the Austrian Ministry of Sciences START program award, and by the European Union projects MASTERSWITCH and KINACEPT (to G.S. and J.-P.D.).

² Address correspondence and reprint requests to Dr. Jean-Pierre David, Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany. E-mail address: jean-pierre.david{at}uk-erlangen.de

³ Abbreviations used in this paper: RA, rheumatoid arthritis; poly(I:C), polyinosinic-polycytidylic acid; TRAP, tartrate-resistant acid phosphatase; MAPKAP, MAPK-activated protein; MKK, MAPK kinase.