JNK/c-Jun signaling mediates an anti-apoptotic effect of RANKL in osteoclasts
JNK/c-Jun signaling mediates an anti-apoptotic effect of RANKL in osteoclasts
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DOI：
10.1359/jbmr.080211
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发表时间：
2008-06-01
影响因子：
6.2
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Ikeda, Fumiyo;Matsubara, Takuma;Yoneda, Toshiyuki
引言：已知RANKL不仅对破骨细胞的分化和活化很重要，而且对其存活也很重要。在实验上，破骨细胞的凋亡是由RANKL的剥夺迅速诱导。RANKL通过TRAF 6激活破骨细胞和前体细胞中的Elk相关酪氨酸激酶（ERK）、p38、c-Jun N-末端激酶（JNK）和NF-κ B通路。已经表明ERK对于调节破骨细胞存活至关重要。然而，其他RANKL信号传导途径如JNK信号传导参与破骨细胞的存活尚未完全了解。通过可溶性RANKL（sRANKL）从原代小鼠骨髓细胞衍生的破骨细胞用JNK抑制剂SP 600125处理，或用携带显性阴性（DN）-c-jun、DN-c-fos、丝裂原活化蛋白激酶激酶1（MEKK 1）1-κ B α突变体，或NF-κ B组分，p50和p65。结果：TRAF 6过表达激活JNK和NF-κ B B信号通路，明显抑制sRANKL缺失引起的破骨细胞凋亡。RANKL/RANK/TRAF 6信号传导对破骨细胞的抗凋亡作用被JNK特异性抑制剂SP 600125和显性负性JNK 1、c-jun和c-fos过表达抑制。此外，MEKK 1的过表达抑制破骨细胞的凋亡，即使在sRANKL沿着JNK/c-jun信号转导激活的情况下。另一方面，I-κ B α突变体或NF-κ B组分过表达对NF-κ B信号传导的阻断对破骨细胞凋亡的影响很小。结论：RANKL诱导的MEKK 1/JNK/c-jun信号传导的激活在破骨细胞凋亡的调节中起重要作用。我们的研究表明，c-fos作为激活蛋白-1因子，c-jun，在破骨细胞凋亡的调节过程中的合作伙伴发挥作用。
Introduction: RANKL is known to be important not only for differentiation and activation of osteoclasts but also for their survival. Experimentally, apoptosis of osteoclasts is rapidly induced by the deprivation of RANKL. RANKL activates Elk-related tyrosine kinase (ERK), p38, c-Jun N-terminal kinase (JNK), and NF-kappa B pathways through TRAF6 in osteoclasts and the precursor cells. It has been shown that ERK is critical for regulation of osteoclast survival. However, an involvement of other RANKL signaling pathways such as JNK signaling in survival of osteoclasts has not been fully understood yet.Materials and Methods: Osteoclasts derived from primary mouse bone marrow cells by soluble RANKL (sRANKL) were treated with a JNK inhibitor, SP600125, or infected with adenovirus carrying dominant-negative (DN)-c-jun, DN-c-fos, mitogen-activated protein kinase kinase 1 (MEKK1), 1-kappa B alpha mutant, or NF-kappa B components, p50 and p65. Osteoclasts were cultured with or without sRANKL, and apoptotic phenotype was determined by TUNEL assay, DAPI staining, and expression of cleaved caspase 3 followed by TRACP staining.Results: Overexpression of TRAF6 activated JNK and NF-kappa B signaling pathways and clearly prevented osteoclasts from apoptosis caused by abrogation of sRANKL. An anti-apoptotic effect of RANKL/RANK/TRAF6 signaling on osteoclast was inhibited by JNK-specific inhibitor SP600125 and by overexpression of dominant-negative JNK1, c-jun, and c-fos. Also, overexpression of MEKK1 inhibited apoptosis of osteoclasts even in the absence of sRANKL along with activation of JNK/c-jun signaling. On the other hand, blockade of NF-kappa B signaling by I-kappa B alpha mutant or overexpression of NF-kappa B components showed a marginal effect on apoptosis of osteoclasts.Conclusions: An important role of RANKL-induced activation of MEKK1/JNK/c-jun signaling in the regulation of apoptosis in osteoclasts was shown. Our study suggests that c-fos plays a role as a partner of activator protein-1 factor, c-jun, during the regulation of apoptosis in osteoclasts.