JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms

TY - JOUR

T1 - JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms

AU - David, Jean-Pierre

AU - Sabapathy, Kanaga

AU - Hoffmann, Oskar

AU - Idarraga, Maria H

AU - Wagner, Erwin F

PY - 2002/11/15

Y1 - 2002/11/15

N2 - Phosphorylation of the N-terminal domain of Jun by the Jun kinases (JNKs) modulates the transcriptional activity of AP-1, a dimeric transcription factor typically composed of c-Jun and c-Fos, the latter being essential for osteoclast differentiation. Using mice lacking JNK1 or JNK2, we demonstrate that JNK1, but not JNK2, is specifically activated by the osteoclast-differentiating factor RANKL. Activation of JNK1, but not JNK2, is required for efficient osteoclastogenesis from bone marrow monocytes (BMMs). JNK1 protects BMMs from RANKL-induced apoptosis during differentiation. In addition, BMMs from mice carrying a mutant of c-Jun phosphorylation sites (JunAA/JunAA), as well as cells lacking either c-Jun or JunD, which is another JNK substrate, revealed that c-Jun phosphorylation and c-Jun itself, but not JunD, are essential for efficient osteoclastogenesis. Moreover, JNK1-dependent c-Jun phosphorylation in response to RANKL is not involved in the anti-apoptotic function of JNK1. Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms.

AB - Phosphorylation of the N-terminal domain of Jun by the Jun kinases (JNKs) modulates the transcriptional activity of AP-1, a dimeric transcription factor typically composed of c-Jun and c-Fos, the latter being essential for osteoclast differentiation. Using mice lacking JNK1 or JNK2, we demonstrate that JNK1, but not JNK2, is specifically activated by the osteoclast-differentiating factor RANKL. Activation of JNK1, but not JNK2, is required for efficient osteoclastogenesis from bone marrow monocytes (BMMs). JNK1 protects BMMs from RANKL-induced apoptosis during differentiation. In addition, BMMs from mice carrying a mutant of c-Jun phosphorylation sites (JunAA/JunAA), as well as cells lacking either c-Jun or JunD, which is another JNK substrate, revealed that c-Jun phosphorylation and c-Jun itself, but not JunD, are essential for efficient osteoclastogenesis. Moreover, JNK1-dependent c-Jun phosphorylation in response to RANKL is not involved in the anti-apoptotic function of JNK1. Thus, these data provide genetic evidence that JNK1 activation modulates osteoclastogenesis through both c-Jun-phosphorylation-dependent and -independent mechanisms.

KW - Animals

KW - Apoptosis

KW - Binding Sites

KW - Bone Marrow Cells

KW - Cell Differentiation

KW - Cells, Cultured

KW - Glycoproteins

KW - Mice

KW - Mice, Knockout

KW - Mitogen-Activated Protein Kinase 8

KW - Mitogen-Activated Protein Kinase 9

KW - Mitogen-Activated Protein Kinases

KW - Monocytes

KW - Mutation

KW - Myeloid Progenitor Cells

KW - Osteoclasts

KW - Osteoprotegerin

KW - Phosphorylation

KW - Proto-Oncogene Proteins c-jun

KW - Receptors, Cytoplasmic and Nuclear

KW - Receptors, Tumor Necrosis Factor

KW - Transcription Factor AP-1

M3 - SCORING: Journal article

C2 - 12376563

VL - 115

SP - 4317

EP - 4325

JO - J CELL SCI

JF - J CELL SCI

SN - 0021-9533

IS - Pt 22

ER -