Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
FASEB J. 2023 Jun;37(6):e22947. doi: 10.1096/fj.202201958R.
The relationship of obesity and osteoporosis has been widely studied over the past years. However, the implications of obesity for bone health remain controversial, and the underlying molecular mechanism is not yet fully understood. This study demonstrated that high-fat diet-induced obesity leads to significantly decreased bone volume/tissue volume (BV/TV), trabecular number (Tb.N), and cortical thickness (Ct.Th) of male rat femur after mechanical loading effects of body weight were controlled. HFD-induced obese rats exhibited attenuated expression of ferroptosis inhibitory protein SLC7A11 and GPX4 in bone tissues, which was correlated with elevated serum TNF-α concentration. Ferroptosis inhibitor administration could effectively rescue decreased osteogenesis-associated type H vessels and osteoprogenitors, and downregulate serum levels of TNF-α to ameliorate bone loss in obese rats. Since ferroptosis and TNF-α both affect bone and vessel formation, we further investigated the interaction between ferroptosis and TNF-α, and its impact in osteogenesis and angiogenesis in vitro. In human osteoblast-like MG63 and umbilical vein endothelial cells (HUVEC), TNF-α/TNFR2 signaling promoted cystine uptake and GSH biosynthesis to provide protection against low-dose ferroptosis inducer erastin. While, TNF-α/TNFR1 facilitated ferroptosis in the presence of high-dose erastin through ROS accumulation. Moreover, TNF-α regulated ferroptosis-induced osteogenic and angiogenic dysfunctions based on its ferroptosis regulatory role. Meanwhile, ferroptosis inhibitors could reduce intracellular ROS overproduction and enhance osteogenesis and angiogenesis in TNF-α-treated MG63 and HUVECs. This study revealed the interaction between ferroptosis and TNF-α and its impact in osteogenesis and angiogenesis, which provides new insights into the pathogenesis and regenerative therapy of obesity-related osteoporosis.
肥胖与骨质疏松症的关系近年来已得到广泛研究。然而，肥胖对骨骼健康的影响仍存在争议，其潜在的分子机制尚不完全清楚。本研究表明，在控制体重的机械加载作用后，高脂肪饮食诱导的肥胖导致雄性大鼠股骨的骨量/组织量（BV/TV）、骨小梁数量（Tb.N）和皮质厚度（Ct.Th）显著减少。HFD 诱导的肥胖大鼠的骨组织中抑制铁死亡的蛋白 SLC7A11 和 GPX4 的表达减弱，这与血清 TNF-α 浓度升高有关。铁死亡抑制剂的给药可有效挽救肥胖大鼠中减少的成骨相关的 H 型血管和前体细胞，并下调血清 TNF-α 水平以改善骨丢失。由于铁死亡和 TNF-α 均影响骨骼和血管的形成，我们进一步研究了铁死亡和 TNF-α 之间的相互作用及其对体外成骨和血管生成的影响。在人成骨样 MG63 和脐静脉内皮细胞（HUVEC）中，TNF-α/TNFR2 信号通过胱氨酸摄取和 GSH 生物合成促进铁死亡抵抗低剂量铁死亡诱导剂 erastin。然而，在存在高剂量 erastin 的情况下，TNF-α/TNFR1 通过 ROS 积累促进铁死亡。此外，TNF-α 基于其铁死亡调节作用调节铁死亡诱导的成骨和血管生成功能障碍。同时，铁死亡抑制剂可减少细胞内 ROS 的过度产生，并增强 TNF-α 处理的 MG63 和 HUVEC 中的成骨和血管生成。本研究揭示了铁死亡与 TNF-α 之间的相互作用及其对成骨和血管生成的影响，为肥胖相关骨质疏松症的发病机制和再生治疗提供了新的见解。
