Dexamethasone suppresses Smad3 pathway in osteoblastic cells
Dexamethasone suppresses Smad3 pathway in osteoblastic cells
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DOI：
10.1677/joe.1.05962
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发表时间：
2005-04-01
影响因子：
4
通讯作者：
Chihara, K
中科院分区：
文献类型：
--
作者：
Iu, MF;Kaji, H;Chihara, K
糖皮质激素（GC）诱导的骨质疏松症发病机制的中心是GC对骨形成的影响。然而，gc抑制骨形成的机制尚不清楚。与其他组织相比，转化生长因子(TGF)- β在骨基质中含量最多，我们最近提出TGF- β信号分子Smad3在促进骨形成中起重要作用。然而，没有关于GC对成骨细胞Smad3影响的报道。在本研究中，我们研究了活性GC类似物地塞米松（dexamethasone, Dex）是否会影响小鼠成骨细胞MC3T3-E1和大鼠成骨细胞UMR-106中Smad3的表达和活性。Dex显著抑制smad3刺激的碱性磷酸酶（ALP）活性，但不影响tgf - β抑制的MC3T3-E1细胞ALP活性。此外，在MC3T3-E1和UMR-106细胞中，Dex预处理可抑制tgf - β增强的I型胶原表达。在带有Smad3特异性应答元件的p3TP-Lux荧光素酶实验中，Dex显著抑制了tgf - β和Smad3诱导的转录活性。然而，Dex在mRNA和蛋白水平上均未影响Smad3在这些细胞中的表达。总之，本研究表明，Dex抑制ALP活性和I型胶原表达，可能是通过抑制Smad3诱导的转录活性，而不是通过调节Smad3在成骨细胞中的表达。
Central in the pathogenesis of glucocorticoid (GC)induced osteoporosis is the effects of GC on bone formation. However, the mechanism of GC-inhibited bone formation is not well known. Transforming growth factor (TGF)-beta is most abundant in bone matrix compared with other tissues, and we have recently proposed that Smad3, a TGF-beta signaling molecule, is important for promoting bone formation. However, no reports have been available about the effects of GC on Smad3 in osteoblasts. In the present study, we investigated whether dexamethasone (Dex), an active GC analog, would affect the expression and activity of Smad3 in mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Dex significantly suppressed Smad3-stimulated alkaline phosphatase (ALP) activity, although it did not affect TGF-beta-inhibited ALP activity in MC3T3-E1 cells. Moreover, pretreatment with Dex suppressed TGF-beta-enhanced expression of type I collagen in MC3T3-E1 and UMR-106 cells. In the luciferase assay using p3TP-Lux with a Smad3-specific response element, Dex significantly suppressed the transcriptional activity induced by TGF-beta as well as Smad3. However, Dex did not affect the expression of Smad3 in these cells at both mRNA and protein levels. In conclusion, the present study indicates that Dex inhibits ALP activity and type I collagen expression, presumably by suppressing Smad3-induced transcriptional activity but not by modulating Smad3 expression in osteoblastic cells.