Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption.
Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption.
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DOI：
10.1038/srep22378
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发表时间：
2016-03-02
影响因子：
4.6
通讯作者：
Chiu RH
中科院分区：
文献类型：
--
作者：
Guo M;James AW;Kwak JH;Shen J;Yokoyama KK;Ting K;Soo CB;Chiu RH
CypA（亲环蛋白 A）是一种肽基-脯氨酰异构酶，之前已被证明是软骨分化和软骨内骨化所必需的。然而，CypA 对破骨细胞活性和骨维持的影响完全未知。在这里，我们发现 Ppia−/− 小鼠表现出骨矿物质密度低、成骨细胞数量减少和破骨细胞数量增加。当从颅骨中分离出来时，Ppia−/− 成骨细胞表现出成骨分化降低，而源自长骨的 Ppia−/− 破骨细胞表现出破骨活性增加。 CypA 的过度表达和基因沉默证实了其成骨和抗破骨作用。在成骨细胞中，CypA 对于 BMP-2（骨形态发生蛋白 2）诱导的 Smad 磷酸化是必需的。在破骨细胞中，CypA 的缺失会激活 BtK（布鲁顿酪氨酸激酶），随后与 TRAF6（TNF 受体相关因子 6）和/或 c-fos 信号整合，诱导 NFATc1（激活 T 细胞的核因子，细胞质 1）。总的来说，CypA 具有促成骨和抗破骨的双重作用。因此，CypA 的调节可能在未来针对骨质疏松症的努力中有用。
CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia−/− mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia−/− osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia−/− osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton’s tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c-fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis.