Q Guo1, D Zhu1, Y Wang1, Z Miao1, Z Chen1, Z Lin1, J Lin1, C Huang1, L Pan2, L Wang1, S Zeng3, J Wang1, X Zheng4, Y Lin5, X Zhang6, Y Wu7. 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. 2. Tianjin University of Traditional Chinese Medicine, Tianjin, China. 3. The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. 4. Department of Vascular Surgery, The Second Affiliated Hospital & Yuying Ghildren's Hospital of Wenzhou Medical University, China. 5. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Electronic address: wzlinyan@126.com. 6. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, China. Electronic address: zhangxiaolei@wmu.edu.cn. 7. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Electronic address: wuyaosen@wmu.edu.cn.
Abstract
OBJECTIVE: DNA damage induced by ROS is considered one of the main causes of nucleus pulposus (NP) cells degeneration during the progression of intervertebral disc degeneration (IVDD). cGAS-STING pathway acts as DNA-sensing mechanism for monitoring DNA damage. Recent studies have proved that cGAS-STING contributes to the development of various diseases by inducing inflammation, senescence, and apoptosis. This work explored the role of STING, the main effector of cGAS-STING signaling pathway, in NP degeneration. METHOD: Immunohistochemistry was conducted to measure STING protein levels in the nucleus pulposus tissues from human and puncture-induced IVDD rat models. TBHP induces degeneration of nucleus pulposus cells in vitro. For in vivo experiments, lv-NC or lv-STING were injected into the central intervertebral disc space. The degeneration level of IVDD was assessed by MRI, X-ray, HE, and Safranin O staining. RESULTS: We found that the expression of STING was upregulated in human and rat degenerated NP tissue as well as in TBHP-treated NP cells. Overexpression of STING promoted the degradation of extracellular matrix; it also promoted apoptosis and senescence of TBHP-treated and untreated NP cells. Knock-down of STING significantly reversed these effects. Mechanistically, STING activated IRF3, whereas blockage of IRF3 attenuated STING-induced apoptosis, senescence and ECM degradation. In vivo experiments revealed that STING knock-down alleviated puncture-induced IVDD development. CONCLUSION: STING promotes IVDD progress via IRF3, while suppression of STING may be a promising treatment for IVDD.
OBJECTIVE: DNA damage induced by ROS is considered one of the main causes of nucleus pulposus (NP) cells degeneration during the progression of intervertebral disc degeneration (IVDD). cGAS-STING pathway acts as DNA-sensing mechanism for monitoring DNA damage. Recent studies have proved that cGAS-STING contributes to the development of various diseases by inducing inflammation, senescence, and apoptosis. This work explored the role of STING, the main effector of cGAS-STING signaling pathway, in NP degeneration. METHOD: Immunohistochemistry was conducted to measure STING protein levels in the nucleus pulposus tissues from human and puncture-induced IVDD rat models. TBHP induces degeneration of nucleus pulposus cells in vitro. For in vivo experiments, lv-NC or lv-STING were injected into the central intervertebral disc space. The degeneration level of IVDD was assessed by MRI, X-ray, HE, and Safranin O staining. RESULTS: We found that the expression of STING was upregulated in human and rat degenerated NP tissue as well as in TBHP-treated NP cells. Overexpression of STING promoted the degradation of extracellular matrix; it also promoted apoptosis and senescence of TBHP-treated and untreated NP cells. Knock-down of STING significantly reversed these effects. Mechanistically, STING activated IRF3, whereas blockage of IRF3 attenuated STING-induced apoptosis, senescence and ECM degradation. In vivo experiments revealed that STING knock-down alleviated puncture-induced IVDD development. CONCLUSION: STING promotes IVDD progress via IRF3, while suppression of STING may be a promising treatment for IVDD.
Authors: Bogdan Costăchescu; Adelina-Gabriela Niculescu; Raluca Ioana Teleanu; Bogdan Florin Iliescu; Marius Rădulescu; Alexandru Mihai Grumezescu; Marius Gabriel Dabija Journal: Int J Mol Sci Date: 2022-06-09 Impact factor: 6.208