The alpha-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 p38alpha and p38beta, and sometimes also other kinases such as JNK3. We show in this study that p38alpha is the main p38 isoenzyme expressed in the osteoclast precursors and in the mature osteoclasts. p38alpha 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 p38alpha 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-1beta expression in the inflamed tissue and in the isolated monocytes. The phenotype was cell autonomous because, similarly to p38alpha-deficient cells, knockdown of p38alpha 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-kappaB activation caused by a decrease in IkappaBalpha 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.
Böhm
Christina
C
Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Hayer
Silvia
S
Kilian
Anita
A
Zaiss
Mario M
MM
Finger
Susann
S
Hess
Andreas
A
Engelke
Klaus
K
Kollias
George
G
Krönke
Gerhard
G
Zwerina
Jochen
J
Schett
Georg
G
David
Jean-Pierre
JP
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000473:pathology; D001862:Bone Resorption / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology; D013379:Substrate Specificity / Q000276:immunology
D007527:Isoenzymes; D048308:Mitogen-Activated Protein Kinase 14