Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.
Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate.
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DOI：
10.1016/j.cmet.2017.01.001
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发表时间：
2017-03-07
期刊：
影响因子：
29
通讯作者：
Lanske B
中科院分区：
文献类型：
--
作者：
Fan Y;Hanai JI;Le PT;Bi R;Maridas D;DeMambro V;Figueroa CA;Kir S;Zhou X;Mannstadt M;Baron R;Bronson RT;Horowitz MC;Wu JY;Bilezikian JP;Dempster DW;Rosen CJ;Lanske B
间歇性甲状旁腺激素管理建立骨量和预防骨折，但其作用机制尚不清楚。我们使用Prx 1Cre基因删除了间充质干细胞中的PTH/PTHrP受体（PTH 1 R），发现骨形成低，骨吸收增加和骨髓脂肪组织（BMAT）高。骨髓脂肪细胞可追溯至Prx 1，并表达经典的脂肪形成标记物和核因子κ-B配体（Rankl）表达的高受体激活剂。骨髓上清液和血清中的RANKL水平也升高，但在其他脂肪库中检测不到。通过细胞分选，突变骨髓中的Pref 1 +RANKL+骨髓祖细胞是对照骨髓的两倍。对对照小鼠间歇性给予PTH显著降低了BMAT。在男性糖尿病患者中观察到类似的发现。因此，骨髓脂肪细胞表现出成骨和成脂特性，对PTH有独特的反应，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的治疗作用的重要机制。XXX等人表明，PTH调节骨髓中骨和脂肪细胞之间的间充质干细胞命运。骨髓脂肪细胞具有与其他脂肪细胞不同的起源和特性，并且对PTH有反应，这是用PTH治疗的小鼠模型和特发性骨质疏松症患者中骨髓肥胖减少的基础。
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, Pref1+RANKL+ 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 osteoporotics. 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. XXX et al show that PTH regulates mesenchymal stem cell fate between bone and adipocyte in the marrow. Bone marrow adipocytes have distinct origins and properties from other adipocytes and are responsive to PTH, underlying the reduction in marrow adiposity in mouse models and idiopathic osteoporosis patients treated with PTH.