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The α-Isoform of p38 MAPK Specifically Regulates Arthritic Bone Loss1

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 p38α and p38β, and sometimes also other kinases such as JNK3. We show in this study that p38α is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38α as well as its downstream substrates were phosphorylated in osteoclast progenitors stimulated by TNF-α. Using Mx-cre-mediated conditional gene inactivation we demonstrated that mice lacking p38α were protected against TNF-α-induced bone destruction at the site of inflammation as well as against TNF-α-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 p38α-deficient cells, knockdown of p38α 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-κB activation caused by a decrease in IκBα recovery. Thus, our data show that developing specific inhibitors of the α-isoenzyme of p38 would be beneficial for the treatment of inflammation-induced bone destruction as observed in rheumatoid arthritis.