Department of Basic Sciences, School of Dentistry, São Paulo State University-UNESP, Araçatuba, São Paulo, Brazil.
Department of Basic Sciences, Programa de Pós-graduação Multicêntrico em Ciências Fisiológicas-SBFIs, School of Dentistry, São Paulo State University-UNESP, Araçatuba, São Paulo, Brazil.
J Cell Physiol. 2018 Sep;233(9):6853-6865. doi: 10.1002/jcp.26445. Epub 2018 Mar 25.
We evaluated whether genetic predisposition is sufficient to induce changes due to chronic high glucose (HG; 25 mmol/L) in the presence or absence of insulin (HGI; 10 μg/ml) on osteogenic differentiation and markers in bone-marrow mesenchymal stem cells (BMSCs) from young Wistar (WBMSCs) and spontaneous hypertensive rats (SBMSCs) without hypertension. HG suppressed osteogenic differentiation in both the strains, observed by mineralization inhibition and decreased levels of the osteogenic markers Runx2, osterix, osteopontin, and bone sialoprotein, compared to osteogenic medium (OM) cells. In WBMSCs, the effects of HG were associated with the down regulation of ERK1/2 and up regulation of p38 activities; however, HGI did not revert the effects of HG on MAPK activities. Moreover, HG did not affect MAPK signaling in SBMSCs compared to that in OM. HGI increased mineralization in WBMSCs compared to that in OM, but not in SBMSCs. High expression of peroxisome proliferator-activated receptor-gamma and glucose transporter type 4 in OM could be related with the predisposition to adipogenic differentiation noted in SBMSCs and was confirmed by emergence of adipocyte-like cells by HGI treatment. Downregulation of p38 and upregulation of JNK activities were observed in both BMSCs treated with HGI compared to those treated by HG. Ma (osmotic control) also suppressed osteogenic differentiation in both the strains. In conclusion, we demonstrated that SBMSCs from young spontaneous hypertensive rats, without hypertension but with genetic and epigenetic predisposition, exhibited decreased osteoblastic differentiation under HG and HGI did not revert the effects of HG in SBMSCs but increased adipogenic differentiation.
我们评估了遗传易感性是否足以在存在或不存在胰岛素（10μg/ml）的情况下，诱导慢性高葡萄糖（HG；25mmol/L）引起的年轻 Wistar（WBMSCs）和自发性高血压大鼠（SBMSCs）骨髓间充质干细胞（BMSCs）的成骨分化和标志物的变化，而这些大鼠没有高血压。与成骨培养基（OM）细胞相比，HG 抑制了两种品系的成骨分化，表现为矿化抑制和成骨标志物 Runx2、osterix、骨桥蛋白和骨唾液蛋白水平降低。在 WBMSCs 中，HG 的作用与 ERK1/2 的下调和 p38 活性的上调有关；然而，HGI 并没有逆转 HG 对 MAPK 活性的影响。此外，与 OM 相比，HG 对 SBMSCs 的 MAPK 信号没有影响。与 OM 相比，HGI 增加了 WBMSCs 的矿化，但对 SBMSCs 没有影响。OM 中过氧化物酶体增殖物激活受体-γ和葡萄糖转运蛋白 4 的高表达可能与 SBMSCs 中注意到的向脂肪分化的易感性有关，并且通过 HGI 处理后出现脂肪细胞样细胞得到证实。与 HG 处理的 BMSCs 相比，HGI 处理的两种 BMSCs 中 p38 的下调和 JNK 活性的上调。Ma（渗透对照）也抑制了两种品系的成骨分化。总之，我们证明了来自年轻自发性高血压大鼠的骨髓间充质干细胞，没有高血压，但具有遗传和表观遗传易感性，在 HG 下表现出成骨细胞分化减少，而 HGI 并没有逆转 HG 在 SBMSCs 中的作用，但增加了脂肪形成分化。
