在许多骨代谢疾病中发现了过量的破骨细胞活性,和抑制破骨细胞分化已被证明是一个有效的策略。这里,我们发现,在核因子κB配体受体激活剂(RANKL)介导的破骨细胞形成过程中,破骨细胞前体(前OCs)对硫氧还蛋白还原酶1(TXNRD1)抑制剂比骨髓来源的单核细胞(BMDMs)更敏感。机械上,我们发现在RANKL诱导的破骨细胞形成过程中,活化T细胞核因子1(NFATc1)通过转录调控上调溶质载体家族7成员11(SLC7A11)的表达.在TXNRD1抑制期间,细胞内二硫化物还原速率显著降低。胱氨酸转运增加导致胱氨酸积累增加,这导致细胞二硫键应激和二硫键沉积增加。我们进一步证明,SLC7A11抑制剂和防止二硫化物积累的治疗方法可以挽救这种类型的细胞死亡。但不是铁凋亡抑制剂(DFO,Ferro-1),ROS清除剂(Trolox,Tempol),凋亡抑制剂(Z-VAD),坏死凋亡抑制剂(Nec-1),或自噬抑制剂(CQ)。一项体内研究表明,TXNRD1抑制剂增加了骨胱氨酸含量,减少破骨细胞的数量,并减轻卵巢切除(OVX)小鼠模型中的骨丢失。一起,我们的研究结果表明,在破骨细胞分化过程中,NFATc1介导的SLC7A11上调可诱导对TXNRD1抑制剂的靶向代谢敏感性.此外,我们创新性地建议TXNRD1抑制剂,治疗破骨细胞相关疾病的经典药物,通过诱导细胞内胱氨酸积累和随后的二硫化物凋亡来选择性杀死前OCs。
Excess osteoclast activity is found in many bone metabolic diseases, and inhibiting osteoclast differentiation has proven to be an effective strategy. Here, we revealed that osteoclast precursors (pre-OCs) were more susceptible to thioredoxin reductase 1 (
TXNRD1) inhibitors than bone marrow-derived monocytes (BMDMs) during receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis. Mechanistically, we found that nuclear factor of activated T-cells 1 (NFATc1) upregulated solute carrier family 7 member 11 (SLC7A11) expression through transcriptional regulation during RANKL-induced osteoclastogenesis. During
TXNRD1 inhibition, the rate of intracellular disulfide reduction is significantly reduced. Increased cystine transport leads to increased cystine accumulation, which leads to increased cellular disulfide stress and disulfidptosis. We further demonstrated that SLC7A11 inhibitors and treatments that prevent disulphide accumulation could rescue this type of cell death, but not the ferroptosis inhibitors (DFO, Ferro-1), the ROS scavengers (Trolox, Tempol), the apoptosis inhibitor (Z-VAD), the necroptosis inhibitor (Nec-1), or the autophagy inhibitor (CQ). An in vivo study indicated that
TXNRD1 inhibitors increased bone cystine content, reduced the number of osteoclasts, and alleviated bone loss in an ovariectomized (OVX) mouse model. Together, our findings demonstrate that NFATc1-mediated upregulation of SLC7A11 induces targetable metabolic sensitivity to
TXNRD1 inhibitors during osteoclast differentiation. Moreover, we innovatively suggest that
TXNRD1 inhibitors, a classic drug for osteoclast-related diseases, selectively kill pre-OCs by inducing intracellular cystine accumulation and subsequent disulfidptosis.