p21WAF1/CIP1 acts as a brake in osteoblast differentiation
p21WAF1/CIP1 acts as a brake in osteoblast differentiation
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DOI：
10.1359/jbmr.2003.18.5.818
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发表时间：
2003-05-01
影响因子：
6.2
通讯作者：
Basilico, C
中科院分区：
文献类型：
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作者：
Bellosta, P;Masramon, L;Basilico, C
连续成纤维细胞生长因子信号传导抑制原代成骨细胞和成骨细胞系的分化。我们研究了响应成纤维细胞生长因子的几种细胞周期调控分子的表达，发现成纤维细胞生长因子强烈上调p21（WAF 1/CIP 1）的表达，这是一种CDK抑制剂，也参与了细胞凋亡和细胞分化的调节。为了验证p21介导成纤维细胞生长因子对成骨细胞作用的假设，我们研究了在存在或不存在成纤维细胞生长因子的情况下，来自p21缺失小鼠的原代成骨细胞和成骨细胞系的分化。虽然所获得的结果表明，p21不是成纤维细胞生长因子抑制成骨细胞分化的主要介质，我们发现，p21本身作为制动成骨细胞增殖和分化。p21在分化过程中强烈下调，并且在表达活化的FGFR 2的成骨细胞系中高度表达，所述成骨细胞系不分化。p21缺失的成骨细胞比野生型细胞分化更快，更容易受到BMP-2的分化促进作用的影响，并经历增加的分化相关凋亡。此外，瞬时过表达的p21从腺病毒载体延迟的野生型和p21空成骨细胞的分化的开始。这些结果突出了p21在成骨细胞分化中的新功能。
Continuous fibroblast growth factor signaling inhibits the differentiation of primary osteoblasts and osteoblastic cell lines. We studied the expression of several cell cycle regulatory molecules in response to fibroblast growth factor, and found that fibroblast growth factor strongly upregulates the expression of p21(WAF1/CIP1), a CDK inhibitor that has also been implicated in the regulation of apoptosis and cell differentiation. To test the hypothesis that p21 mediated the fibroblast growth factor effects on osteoblasts, we studied the differentiation of primary osteoblasts and osteoblastic cell lines derived from p21 null mice in the presence or absence of fibroblast growth factor. While the results obtained indicate that p21 is not the major mediator of the inhibition of osteoblast differentiation by fibroblast growth factor, we found that p21 per se acts as a brake on osteoblast proliferation and differentiation. p21 is strongly downregulated during differentiation and is highly expressed in osteoblastic cell lines expressing activated FGFR2, which do not differentiate. p21 null osteoblasts differentiate faster than wild-type cells, are more susceptible to the differentiation-promoting action of BMP-2, and undergo increased differentiation-related apoptosis. Furthermore, transient overexpression of p21 from an adenovirus vector delayed the onset of differentiation both in wild-type and in p21 null osteoblasts. These results highlight a new function for p21 in osteoblast differentiation.