The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss

TY - JOUR

T1 - The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss

AU - Böhm, Christina

AU - Hayer, Silvia

AU - Kilian, Anita

AU - Zaiss, Mario M

AU - Finger, Susann

AU - Hess, Andreas

AU - Engelke, Klaus

AU - Kollias, George

AU - Krönke, Gerhard

AU - Zwerina, Jochen

AU - Schett, Georg

AU - David, Jean-Pierre

PY - 2009/11/1

Y1 - 2009/11/1

N2 - 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.

AB - 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.

KW - Animals

KW - Arthritis, Experimental

KW - Bone Resorption

KW - Cell Differentiation

KW - Cell Lineage

KW - Cells, Cultured

KW - Humans

KW - Isoenzymes

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Mitogen-Activated Protein Kinase 14

KW - Osteoclasts

KW - Substrate Specificity

U2 - 10.4049/jimmunol.0901026

DO - 10.4049/jimmunol.0901026

M3 - SCORING: Journal article

C2 - 19828631

VL - 183

SP - 5938

EP - 5947

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 9

ER -