Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis
Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis
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DOI：
10.1634/stemcells.2008-0127
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发表时间：
2008-09-01
期刊：
影响因子：
5.2
通讯作者：
Amri, Ez-Zoubir
中科院分区：
文献类型：
--
作者：
Elabd, Christian;Basillais, Armelle;Amri, Ez-Zoubir
骨质疏松症是一个主要的全球性公共卫生负担，其特征是骨骼脆弱性增加。骨代谢是破骨细胞的骨吸收和成骨细胞的骨形成的组合。尽管骨吸收的增加被认为是可能导致骨质疏松症的骨丢失的主要因素，但这种丢失伴随着骨髓肥胖的增加。成骨细胞和脂肪细胞共享相同的前体细胞，并且在两个谱系之间存在相反的关系。因此，识别刺激间充质干细胞以脂肪生成为代价的成骨的信号通路对于开发新的治疗方法具有重要意义。为此，我们通过转录组学分析确定了催产素受体途径作为人多能脂肪干细胞（hMADS）成骨细胞/脂肪细胞平衡的潜在调节因子。催产素（OT）和卡贝缩宫素（一种稳定的OT类似物）负调节脂肪生成，同时促进hMADS细胞和人骨髓间充质基质细胞中的骨生成。与这些观察结果相一致，卵巢切除（OVX）小鼠和大鼠，变得肥胖并表现出这种平衡的不平衡，与假手术对照组相比，OT水平显著降低。皮下注射OT可逆转OVX小鼠的骨丢失并减少骨髓肥胖。临床上，血浆OT水平显着低于绝经后妇女发展骨质疏松症比健康的同行。总之，这些结果表明，血浆OT水平代表了骨质疏松症的一种新的诊断标志物，OT给药有望成为这种疾病的潜在治疗方法。
Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin ( a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.