p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function
p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function
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DOI：
10.1210/en.143.8.3105
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发表时间：
2002-08-01
期刊：
影响因子：
4.8
通讯作者：
Takahashi, N
中科院分区：
文献类型：
--
作者：
Li, XT;Udagawa, N;Takahashi, N
核因子-κ B受体激活因子配体（RANKL）诱导的信号在破骨细胞的分化和功能中起关键作用。p38 AMPK抑制剂SB 203580可阻断1 α，25-二羟维生素D-3和前列腺素E-2诱导的小鼠成骨细胞和骨髓细胞共培养中破骨细胞的形成。然而，SB 203580对用la，25-二羟基维生素D和前列腺素E2处理的成骨细胞中的RANKL表达没有抑制作用。骨髓培养物中RANKL诱导的破骨细胞生成被SB 203580抑制，表明SB 203580在破骨细胞分化中对破骨细胞前体细胞有直接影响，但对成骨细胞无直接影响。然而，SB 203580既不抑制RANKL诱导的破骨细胞的存活，也不抑制破骨细胞的牙本质吸收活性。脂多糖（LPS）、IL-1和TNF α均刺激破骨细胞的存活，这不被SB 203580抑制。RANKL、IL-1、TNF α和LPS在破骨细胞前体中诱导p38 MAPK磷酸化，但在破骨细胞中不诱导。LPS刺激MAPK激酶3/6和ATF 2的磷酸化，分别在破骨细胞前体中，但在破骨细胞中没有。然而，LPS诱导破骨细胞和破骨细胞前体中IkappaB的降解和ERK的磷酸化。这些结果表明，破骨细胞的功能是通过一种机制，独立于p38 MAPK介导的信号转导。
Receptor activator of nuclear factor-kappaB ligand (RANKL)induced signals play critical roles in osteoclast differentiation and function. SB203580, an inhibitor of p38 AMPK, blocked osteoclast formation induced by 1alpha,25-dihydroxyvitamin D-3 and prostaglandin E-2 in cocultures of mouse osteoblasts and bone marrow cells. Nevertheless, SB203580 showed no inhibitory effect on RANKL expression in osteoblasts treated with la,25-dihydroxyvitamin D, and prostaglandin E2. RANKL-induced osteoclastogenesis in bone marrow cultures was inhibited by SB203580, suggesting a direct effect of SB203580 on osteoclast precursors, but not on osteoblasts, in osteoclast differentiation. However, SB203580 inhibited neither the survival nor dentine-resorption activity of osteoclasts induced by RANKL. Lipopolysaccharide (LPS), IL-1, and TNFalpha all stimulated the survival of osteoclasts, which was not inhibited by SB203580. Phosphorylation of p38 MAPK was induced by RANKL, IL-1, TNFa, and LPS in osteoclast precursors but not in osteoclasts. LPS stimulated phosphorylation of MAPK kinase 3/6 and ATF2, upstream and downstream signals of p38 MAPK, respectively, in osteoclast precursors but not in osteoclasts. Nevertheless, LPS induced degradation of IkappaB and phosphorylation of ERK in osteoclasts as well as in osteoclast precursors. These results suggest that osteoclast function is induced through a mechanism independent of p38 MAPK-mediated signaling.