David Jean-Pierre, Sabapathy Kanaga, Hoffmann Oskar, Idarraga Maria H, Wagner Erwin F
Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, A-1030 Vienna, Austria.
J Cell Sci. 2002 Nov 15;115(Pt 22):4317-25. doi: 10.1242/jcs.00082.
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.
JNK激酶（JNKs）介导的Jun蛋白N端结构域磷酸化可调节AP-1的转录活性，AP-1是一种二聚体转录因子，通常由c-Jun和c-Fos组成，后者对破骨细胞分化至关重要。利用缺乏JNK1或JNK2的小鼠，我们发现JNK1而非JNK2可被破骨细胞分化因子RANKL特异性激活。骨髓单核细胞（BMMs）高效分化为破骨细胞需要激活JNK1而非JNK2。JNK1可保护BMMs在分化过程中免受RANKL诱导的凋亡。此外，携带c-Jun磷酸化位点突变体（JunAA/JunAA）的小鼠的BMMs，以及缺乏c-Jun或另一个JNK底物JunD的细胞表明，c-Jun磷酸化和c-Jun本身而非JunD对高效破骨细胞生成至关重要。此外，RANKL诱导的依赖JNK1的c-Jun磷酸化不参与JNK1的抗凋亡功能。因此，这些数据提供了遗传学证据，表明JNK1激活通过c-Jun磷酸化依赖和非依赖机制调节破骨细胞生成。
