Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin- related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-TERT). RSV (1.0 μM) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-TERT when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using PF-573228 (5 μM), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.

中文翻译：

---

白藜芦醇抑制人骨髓基质干细胞的脂肪细胞分化和细胞衰老

骨髓脂肪组织 (BMAT) 是一种独特的脂肪库，源自骨髓基质干细胞 (BMSC)，可调节骨稳态和能量代谢。在多种情况下观察到 BMAT 体积增加，例如肥胖、2 型糖尿病、骨质疏松症，并且已知与骨脆性和骨折风险增加有关。减少 BMAT 积累的治疗方法具有临床意义。在天然化合物的筛选实验中，我们鉴定了白藜芦醇 (RSV)，这是一种植物来源的抗氧化剂，通过 Sirtuin 相关机制介导生物效应，对 BMAT 形成产生显着影响。因此，我们详细检查了 RSV 对耐受性人 BMSC (hBMSC-TERT) 的脂肪细胞和成骨细胞分化的影响。回复 (1。0 μM) 与对照和 Sirtinol（Sirtuin 抑制剂）相比，增强了 hBMSC-TERT 的成骨细胞分化并抑制了脂肪细胞分化。全球基因表达谱和蛋白质印迹分析揭示了许多信号通路的激活，包括粘着斑激酶 (FAK)。使用 PF-573228 (5 μM) 对 FAK 的药理学抑制减少了 RSV 诱导的成骨细胞分化。此外，RSV 降低了衰老相关分泌表型 (SASP)、与衰老相关的基因标志物（P53、P16 和 P21）、细胞内 ROS 水平和保护细胞免受氧化损伤的酶（HMOX1 和 SOD3）的基因表达增加的水平. 用 RSV 体外治疗具有高脂肪细胞和低成骨细胞分化能力的原代 hBMSCs，显着增强成骨细胞并减少脂肪细胞形成。RSV 靶向 hBMSCs 并抑制脂肪形成分化和衰老相关表型，因此是治疗 BMAT 形成增加的疾病的潜在药物。