Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.
Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.
复制标题
DOI：
10.1038/ncomms6215
复制
发表时间：
2014-10-21
影响因子：
16.6
通讯作者：
Amling, Michael
中科院分区：
文献类型：
--
作者：
Keller, Johannes;Catala-Lehnen, Philip;Huebner, Antje K.;Jeschke, Anke;Heckt, Timo;Lueth, Anja;Krause, Matthias;Koehne, Till;Albers, Joachim;Schulze, Jochen;Schilling, Sarah;Haberland, Michael;Denninger, Hannah;Neven, Mona;Hermans-Borgmeyer, Irm;Streichert, Thomas;Breer, Stefan;Barvencik, Florian;Levkau, Bodo;Rathkolb, Birgit;Wolf, Eckhard;Calzada-Wack, Julia;Neff, Frauke;Gailus-Durner, Valerie;Fuchs, Helmut;de Angelis, Martin Hrabe;Klutmann, Susanne;Tsourdi, Elena;Hofbauer, Lorenz C.;Kleuser, Burkhard;Chun, Jerold;Schinke, Thorsten;Amling, Michael
激素降钙素（CT）主要以其作为骨吸收抑制剂的药理作用而闻名，但CT缺陷小鼠显示骨形成增加。这些发现提出了关于CT作用的潜在细胞和分子机制的问题。在这里，我们表明，无论是无处不在的或破骨细胞特异性的小鼠CT受体（CTR）的失活导致骨形成增加。CT负调节破骨细胞Spns 2基因的表达，该基因编码信号脂质鞘氨醇1-磷酸（S1 P）的转运蛋白。CTR缺陷小鼠显示增加的S1 P水平，其骨骼表型通过S1 P受体S1 P3的缺失而正常化。最后，非选择性S1 P受体激动剂FTY 720的药物治疗导致野生型小鼠骨形成增加，但在S1 P3缺陷小鼠中则不然。这项研究重新定义了CT在骨骼生物学中的作用，证实了S1 P在体内作为骨合成代谢分子，并为破骨细胞和成骨细胞之间可利用的串扰提供了证据。 降钙素在骨稳态中的调节作用已被充分研究，但其分子活性知之甚少。作者表明，降钙素通过抑制破骨细胞分泌1-磷酸鞘氨醇（破骨细胞-成骨细胞串扰的脂质介质）来调节骨细胞功能。
The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.
登录
查看更多内容
DOI：
10.1083/jcb.201207142
发表时间：
2013-02-18
期刊：
The Journal of cell biology
影响因子：
--
作者：
Albers J;Keller J;Baranowsky A;Beil FT;Catala-Lehnen P;Schulze J;Amling M;Schinke T
通讯作者：
Schinke T
影响因子：
56.9
作者：
CHAKRABORTY, M;CHATTERJEE, D;BARON, R
通讯作者：
BARON, R
影响因子：
10.5
作者：
FIERING, S;EPNER, E;GROUDINE, M
通讯作者：
GROUDINE, M
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
20.3
作者：
Allende, ML;Yamashita, T;Proia, RL
通讯作者：
Proia, RL