2. Academic Validation
  3. NFATc1-mediated expression of SLC7A11 drives sensitivity to TXNRD1 inhibitors in osteoclast precursors

NFATc1-mediated expression of SLC7A11 drives sensitivity to TXNRD1 inhibitors in osteoclast precursors

  • Redox Biol. 2023 Jul:63:102711. doi: 10.1016/j.redox.2023.102711.
Zeyuan Zhong 1,  Chongjing Zhang 1,  Shuo Ni 2,  Miao Ma 3,  Xiaomeng Zhang 4,  Weicong Sang 5,  Tao Lv 6,  Zhi Qian 7,  Chengqing Yi 8,  Baoqing Yu 9
Affiliations

Affiliations

  • 1 Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.
  • 2 Department of Orthopedic Surgery and Shanghai Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 3 The Second Clinical Medical College, Lanzhou University, Lanzhou, China.
  • 4 Renal Medicine and Baxter Novum, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
  • 5 Shanghai Medical College, Fudan University, Shanghai, China.
  • 6 Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
  • 7 Institution of Orthopaedic Diseases, Zhangye People's Hospital Affiliated to Hexi University, Zhangye, China. Electronic address: [email protected].
  • 8 Department of Orthopedics, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China. Electronic address: [email protected].
  • 9 Department of Orthopedics, Shanghai Pudong New Area People's Hospital, Shanghai, China. Electronic address: [email protected].
PMID: 37148740 DOI: 10.1016/j.redox.2023.102711
Abstract

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.

Keywords

Disulfidptosis; Metabolic reprogramming; NFATc1; Osteoclast; SLC7A11; TXNRD1.

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