Protein palmitoylation regulates osteoblast differentiation through BMP-induced osterix expression.
Protein palmitoylation regulates osteoblast differentiation through BMP-induced osterix expression.
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DOI：
10.1371/journal.pone.0004135
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Li, Baojie
中科院分区：
文献类型：
--
作者：
Leong, Wai Fook;Zhou, Tielin;Lim, Gek Liang;Li, Baojie
骨质疏松症是最常见的疾病之一，可以通过抗吸收药物，合成代谢药物或两者兼而有之来治疗。为了寻找骨质疏松症治疗的合成代谢药物靶点，了解骨形成细胞，成骨细胞的增殖，分化和功能的生物学是至关重要的。在这里，我们发现蛋白质棕榈酰化参与控制osterix表达和成骨细胞分化的信号通路。小鼠颅骨成骨细胞表达24种棕榈酰转移酶中的大部分，其中一些在分化过程中上调。用底物类似物抑制剂抑制蛋白棕榈酰化，减少成骨细胞分化和矿化，但不增殖或存活。分化能力的降低与osterix的减少有关，但与Runx 2或Atf 4无关。棕榈酰转移酶的抑制对p53−/−成骨细胞几乎没有影响，这些成骨细胞由于osterix的过度表达而表现出加速分化，这表明osterix至少部分介导了棕榈酰转移酶抑制对成骨细胞分化的影响。在分化试验中，BMP是成骨细胞分化的主要驱动力。我们发现，棕榈酰转移酶的抑制也损害BMP 2诱导的成骨细胞分化通过下调osterix诱导。棕榈酰转移酶抑制剂不能抑制Smad 1/5/8的激活。相反，它损害了p38 MAPK的激活，p38 MAPK是osterix表达和分化的已知正调控因子。这些结果表明，蛋白质棕榈酰化在BMP诱导的MAPK激活，osterix表达和成骨细胞分化中起着重要作用。
Osteoporosis is one of the most common diseases and can be treated by either anti-resorption drugs, anabolic drugs, or both. To search for anabolic drug targets for osteoporosis therapy, it is crucial to understand the biology of bone forming cells, osteoblasts, in terms of their proliferation, differentiation, and function. Here we found that protein palmitoylation participates in signaling pathways that control osterix expression and osteoblast differentiation. Mouse calvarial osteoblasts express most of the 24 palmitoyl transferases, with some being up-regulated during differentiation. Inhibition of protein palmitoylation, with a substrate-analog inhibitor, diminished osteoblast differentiation and mineralization, but not proliferation or survival. The decrease in differentiation capacity is associated with a reduction in osterix, but not Runx2 or Atf4. Inhibition of palmitoyl transferases had little effect in p53−/− osteoblasts that show accelerated differentiation due to overexpression of osterix, suggesting that osterix, at least partially, mediated the effect of inhibition of palmitoyl transferases on osteoblast differentiation. BMPs are the major driving force of osteoblast differentiation in the differentiation assays. We found that inhibition of palmitoyl transferases also compromised BMP2-induced osteoblast differentiation through down-regulating osterix induction. However, palmitoyl transferases inhibitor did not inhibit Smad1/5/8 activation. Instead, it compromised the activation of p38 MAPK, which are known positive regulators of osterix expression and differentiation. These results indicate that protein palmitoylation plays an important role in BMP-induced MAPK activation, osterix expression, and osteoblast differentiation.
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影响因子：
4.8
作者：
Celil, AB;Campbell, PG
通讯作者：
Campbell, PG
DOI：
10.1073/pnas.0401367101
发表时间：
2004-04-20
影响因子：
11.1
作者：
Qi, XX;Li, TG;Zhao, GQ
通讯作者：
Zhao, GQ
影响因子：
64.5
作者：
Nakashima, K;Zhou, X;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
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影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
4.8
作者：
Li, BJ;Cong, F;Goff, SP
通讯作者：
Goff, SP