The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss

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 alpha and p38 beta, and sometimes also other kinases such as JNK3. We show in this study that p38 alpha is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38 alpha as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-alpha. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38 alpha were protected against TNF-alpha-induced bone destruction at the site of inflammation as well as against TNF-alpha-mediated systemic bone loss. The bone protection was associated to decreased osteoclast numbers in vivo as well as a decreased IL-1 beta expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38 alpha-deficient cells, knockdown of p38 alpha 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-kappa B activation caused by a decrease in I kappa B alpha recovery. Thus, our data show that developing specific inhibitors of the alpha-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis. The Journal of Immunology, 2009, 183: 5938-5947.