Osteonecrosis of the Femoral Head: Lipotoxicity Exacerbation in MSC and Modifications of the Bone Marrow Fluid
Osteonecrosis of the Femoral Head: Lipotoxicity Exacerbation in MSC and Modifications of the Bone Marrow Fluid
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DOI：
10.1210/en.2016-1687
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发表时间：
2017-03-01
期刊：
影响因子：
4.8
通讯作者：
Rasschaert, Joanne
中科院分区：
文献类型：
--
作者：
Gillet, Celine;Dalla Valle, Antoine;Rasschaert, Joanne
股骨头坏死(ON)是一种多因素的骨病，可发展为髋关节的进行性破坏。不同的致病过程被提出，其中，脂肪细胞积聚导致骨髓(BM)脂肪增加。骨髓脂肪细胞是活跃的骨髓细胞，通过释放细胞因子、脂肪因子和游离脂肪酸(FA)来影响微环境。探讨棕榈酸酯(Palm)和油酸对骨坏死患者(ONMSC)和健康志愿者骨髓间充质基质细胞(MSC)功能和存活的影响。此外，我们还分析了血清和骨髓上清液(BMSF)的FA谱。我们证明，暴露在饱和FA Palm中有利于MSC通过成脂谱系分化，但损害了成骨细胞的表型。此外，ONMSC的成脂作用增强。ONMSC对棕榈毒性的敏感性加重，同时伴随着促凋亡的细胞外信号调节激酶通路的更大激活。此外，在ONMSC中，硬脂酰辅酶A去饱和酶1和肉碱棕榈酰基转移酶1的表达异常是参与抗脂毒性作用的细胞机制之一。手掌诱导的IL-6和IL-8的分泌也在ONMSC中加剧。我们的结果表明，在健康受试者和ON受试者的血清中，FA谱是相似的。然而，ON患者BMSF中FA的浓度和组成都发生了改变，突显了ON患者BM微环境的剧烈变化。综上所述，我们的工作表明，骨髓脂肪细胞的增大可能影响骨重建的过程，从而在ON的发病机制中发挥作用。
Osteonecrosis of the femoral head (ON) is a multifactorial bone disease that can evolve to a progressive destruction of the hip joint. Different pathogenic processes have been proposed, among them, an increase of bone marrow (BM) fat resulting from adipocyte accumulation. Marrow adipocytes are active BM residents that influence the microenvironment by releasing cytokines, adipokines, and free fatty acids (FA). We explored the impact of palmitate (Palm) and oleate on function and survival of BM-derived mesenchymal stromal cells (MSC) of osteonecrotic patients (ONMSC) and healthy volunteers. Moreover, we analyzed the FA profile of the serum and the BM supernatant fluid (BMSF). We demonstrated that exposure to the saturated FA Palm favored MSC differentiation through the adipogenic lineage at the expense of the osteoblastic phenotype. Moreover, adipogenesis was intensified in ONMSC. The susceptibility to Palm toxicity was aggravated in ONMSC concomitantly with a greater activation of the proapoptotic extracellular signal-regulated kinase pathway. Moreover, cellular mechanisms implicated in the protection against lipotoxicity, such as stearoyl-coenzyme A desaturase 1 and carnitine palmitoyl transferase 1 expression, were dysregulated in ONMSC. Palm-induced interleukin (IL)-6 and IL-8 secretion was also exacerbated in ONMSC. Our results established that, in the serum, the FA profiles were comparable in ON and healthy subjects. However, both the concentrations and the FA composition were modified in the BMSF of ON patients, highlighting a drastic change of the BM microenvironment in ON patients. Altogether, our work suggests that marrow adipocyte enlargement could affect the process of bone remodeling and, therefore, play a role in the pathogenesis of ON.