甲状旁腺激素指导骨髓间充质细胞命运。
Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.
作者信息
Fan Yi, Hanai Jun-Ichi, Le Phuong T, Bi Ruiye, Maridas David, DeMambro Victoria, Figueroa Carolina A, Kir Serkan, Zhou Xuedong, Mannstadt Michael, Baron Roland, Bronson Roderick T, Horowitz Mark C, Wu Joy Y, Bilezikian John P, Dempster David W, Rosen Clifford J, Lanske Beate
机构信息
Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA 02115, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
出版信息
Cell Metab. 2017 Mar 7;25(3):661-672. doi: 10.1016/j.cmet.2017.01.001. Epub 2017 Feb 2.
Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1RANKL marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH's therapeutic action through its ability to direct mesenchymal cell fate.
间歇性给予甲状旁腺激素（PTH）可增加骨量并预防骨折，但其作用机制尚不清楚。我们使用Prx1Cre在间充质干细胞中通过基因编辑删除了PTH/PTHrP受体（PTH1R），结果发现骨形成减少、骨吸收增加以及骨髓脂肪组织（BMAT）增多。骨髓脂肪细胞起源于Prx1，并表达经典的脂肪生成标志物以及高水平的核因子κB受体活化因子配体（Rankl）。骨髓上清液和血清中的RANKL水平也升高，但在其他脂肪库中未检测到。通过细胞分选发现，与对照骨髓相比，Pref1RANKL骨髓祖细胞在突变体中数量是其两倍。对对照小鼠间歇性给予PTH可显著减少BMAT。在男性骨质疏松症患者中也观察到了类似的结果。因此，骨髓脂肪细胞具有成骨和成脂特性，对PTH具有独特的反应性，并分泌RANKL。这些研究揭示了PTH通过其指导间充质细胞命运的能力发挥治疗作用的重要机制。
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