The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss
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The alpha-isoform of p38 MAPK specifically regulates arthritic bone loss. / Böhm, Christina; Hayer, Silvia; Kilian, Anita; Zaiss, Mario M; Finger, Susann; Hess, Andreas; Engelke, Klaus; Kollias, George; Krönke, Gerhard; Zwerina, Jochen; Schett, Georg; David, Jean-Pierre.
in: J IMMUNOL, Jahrgang 183, Nr. 9, 01.11.2009, S. 5938-47.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -