Inactivation of Tnf-α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice

Tao, Chu1,2; Lin, Sixiong2,3; Shi, Yujia4; Gong, Weiyuan2,5; Chen, Mingjue2; Li, Jianglong2,6; Zhang, Peijun2; Yao, Qing2; Qian, Dongyang3; Ling, Zemin7; Xiao, Guozhi2

2024-12-01

10.1002/jsp2.70006

JOR SPINE   影响因子和分区

2572-1143

["BackgroundIntervertebral disc degeneration (IVDD) is a major cause of low back pain (LBP), worsened by chronic inflammatory processes associated with aging. Tumor necrosis factor alpha (Tnf-alpha) and its receptors, Tnf receptor type 1 (Tnfr1) and Tnf receptor type 2 (Tnfr2), are upregulated in IVDD. However, its pathologic mechanisms remain poorly defined.MethodsTo investigate the role of Tnfr in IVDD, we generated global Tnfr1/2 double knockout (KO) mice and age-matched control C57BL/6 male mice, and analyzed intervertebral disc (IVD)-related phenotypes of both genotypes under physiological conditions, aging, and lumbar spine instability (LSI) model through histological and immunofluorescence analyses and mu CT imaging. Expression levels of key extracellular matrix (ECM) proteins in aged and LSI mice, especially markers of cell proliferation and apoptosis, were evaluated in aged (21-month-old) mice.ResultsAt 4 months, KO and control mice showed no marked differences of IVDD-related parameters. However, at 21 months of age, the loss of Tnfr expression significantly alleviated IVDD-like phenotypes, including a significant increase in height of the nucleus pulposus (NPs) and reductions of endplates (EPs) porosity and histopathological scores, when compared to controls. Tnfr deficiency promoted anabolic metabolism of the ECM proteins and suppressed ECM catabolism. Tnfr loss largely inhibited hypertrophic differentiation, and, in the meantime, suppressed cell apoptosis and cellular senescence in the annulus fibrosis, NP, and EP tissues without affecting cell proliferation. Similar results were observed in the LSI model, where Tnfr deficiency significantly alleviated IVDD and enhanced ECM anabolic metabolism while suppressing catabolism.ConclusionThe deletion of Tnfr mitigates age-related and LSI-induced IVDD, as evidenced by preserved IVD structure, and improved ECM integrity. These findings suggest a crucial role of Tnf-alpha/Tnfr signaling in IVDD pathogenesis in mice. Targeting this pathway may be a novel strategy for IVDD prevention and treatment.","The study demonstrate a critical role of the Tnf-alpha/Tnfr signaling in promoting age- and LSI-induced IVDD in mice. Targeting this pathway may be a novel strategy to prevent and treat IVDD development and progression. image"]

intervertebral disc degeneration TNF receptor tumor necrosis factor-alpha

SCI

英语

通讯

Shenzhen Key Basic Research and Development Program[JCYJ20220818100617036] ; National Key Research and Development Program of China[2019YFA0906004] ; Guangdong Provincial Science and Technology Innovation Council[2017B030301018] ; Shenzhen Key Laboratory of Cell Microenvironment Grant[ZDSYS20140509142721429] ; null[82230081] ; null[82250710175] ; null[82261160395] ; null[82430078] ; null[81991513]

Orthopedics

Orthopedics

WOS:001328404300001

WILEY

Web of Science

1.Harbin Inst Technol, Sch Life Sci & Technol, Harbin, Peoples R China
2.Southern Univ Sci & Technol, Dept Biochem, Guangdong Prov Key Lab Cell Microenvironm & Dis Re, Shenzhen Key Lab Cell Microenvironm,Sch Med, 1088 Xue Yuan Rd, Shenzhen 518055, Guangdong, Peoples R China
3.Guangzhou Med Univ, Guangdong Key Lab Orthopaed Technol & Implant Mat, Affiliated Hosp 1, Dept Orthopaed, Guangzhou 510120, Peoples R China
4.Chinese Univ Hong Kong, Sch Biomed Sci, Shatin, Hong Kong, Peoples R China
5.Hong Kong Polytech Univ, Dept Biomed Engn, Hung Hom, Hong Kong, Peoples R China
6.Southern Med Univ, Zhujiang Hosp, Dept Orthopaed, Guangzhou, Peoples R China
7.Sun Yat Sen Univ, Affiliated Hosp 7, Dept Orthopaed Surg, Shenzhen Key Lab Bone Tissue Repair & Translat Res, Shenzhen, Peoples R China

Tao, Chu,Lin, Sixiong,Shi, Yujia,et al. Inactivation of Tnf-α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice[J]. JOR SPINE,2024,7(4).

Tao, Chu.,Lin, Sixiong.,Shi, Yujia.,Gong, Weiyuan.,Chen, Mingjue.,...&Xiao, Guozhi.(2024).Inactivation of Tnf-α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice.JOR SPINE,7(4).

Tao, Chu,et al."Inactivation of Tnf-α/Tnfr signaling attenuates progression of intervertebral disc degeneration in mice".JOR SPINE 7.4(2024).