JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms
JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms
复制标题
DOI：
10.1242/jcs.00082
复制
发表时间：
2002-11-15
影响因子：
4
通讯作者：
Wagner, EF
中科院分区：
文献类型：
--
作者：
David, JP;Sabapathy, K;Wagner, EF
Jun激酶（JNK）对Jun N-末端结构域的磷酸化调节AP-1的转录活性，AP-1是典型地由c-Jun和c-Fos组成的二聚体转录因子，后者对于破骨细胞分化是必需的。使用缺乏JNK 1或JNK 2的小鼠，我们证明了JNK 1，而不是JNK 2，被破骨细胞分化因子RANKL特异性激活。JNK 1而非JNK 2的活化是骨髓单核细胞有效破骨细胞生成所必需的。（B.A.）。JNK 1在分化过程中保护Bcl-2免受RANKL诱导的凋亡。此外，来自携带c-Jun磷酸化位点突变体（junAA/JunAA）的小鼠以及缺乏c-Jun或JunD（另一种JNK底物）的细胞的Bctin显示，c-Jun磷酸化和c-Jun本身，而不是JunD，对于有效的破骨细胞生成至关重要。此外，JNK 1依赖性c-Jun磷酸化对RANKL的反应不参与JNK 1的抗凋亡功能。因此，这些数据提供了遗传学证据，JNK 1激活通过c-jun磷酸化依赖性和非依赖性机制调节破骨细胞生成。
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 JNKI, 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.