Calcineurin regulates bone formation by the osteoblast
Calcineurin regulates bone formation by the osteoblast
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DOI：
10.1073/pnas.0508480102
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发表时间：
2005-11-22
影响因子：
11.1
通讯作者：
Zaidi, M
中科院分区：
文献类型：
--
作者：
Sun, L;Blair, HC;Zaidi, M
两种最常用的免疫抑制剂，环孢素 A 和他克莫司 (FK506)，可抑制普遍表达的 Ca2+/钙调蛋白敏感性磷酸酶（钙调神经磷酸酶）的活性。由于这两种药物也会导致人类和动物模型中严重的骨质流失，因此我们探讨了钙调神经磷酸酶是否在调节骨骼重塑中发挥作用。我们发现成骨细胞含有钙调神经磷酸酶 A 和 B 的所有亚型的 mRNA 和蛋白质。 TAT 辅助将融合蛋白 TAT-钙调神经磷酸酶 A α 转导到成骨细胞中，导致成骨细胞分化标志物 Runx-2、碱性磷酸酶、骨唾液酸蛋白和骨钙蛋白的表达增强。这种表达与完整颅骨培养物中骨形成的显着增强有关。钙调神经磷酸酶 A α(-/-) 小鼠表现出严重的骨质疏松症，矿物质沉积率显着降低，并且在 10 天的离体基质细胞培养物中集落形成减弱。后者与 Runx2、骨唾液蛋白和骨钙蛋白表达的显着降低相关，同时 FK506 的反应也出现类似的降低。总之，功能获得和功能丧失实验表明钙调神经磷酸酶通过影响成骨细胞分化来调节骨形成。
Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca2+/calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin A alpha into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin A alpha(-/-) mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain- and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.