2. Academic Validation
  3. GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis

GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis

  • J Adv Res. 2024 Aug 3:S2090-1232(24)00323-0. doi: 10.1016/j.jare.2024.08.001.
Pengfei Zhang 1,  Haoxin Zhai 1,  Shuai Zhang 2,  Xiaojie Ma 3,  Ao Gong 4,  Zhaoning Xu 5,  Wei Zhao 6,  Hui Song 6,  Shufeng Li 7,  Tengfei Zheng 8,  Zhendong Ying 9,  Lei Cheng 10,  Yunpeng Zhao 11,  Lei Zhang 12
Affiliations

Affiliations

  • 1 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 2 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
  • 3 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Department of Rheumatology and Immunology, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
  • 4 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
  • 5 Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 6 Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, Jinan, Shandong 250012, PR China; School of Basic Medical Science, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 7 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong 250012, PR China.
  • 8 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China.
  • 9 Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
  • 10 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China. Electronic address: chenglei@email.sdu.edu.cn.
  • 11 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China. Electronic address: miraculously2008@163.com.
  • 12 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong 250012, PR China; Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, PR China. Electronic address: qygkzl1818@163.com.
PMID: 39103049 DOI: 10.1016/j.jare.2024.08.001
Abstract

Introduction: Osteoarthritis (OA) is a highly prevalent degenerative disease worldwide, and tumor necrosis factor (TNF-α) is closely associated with its development. Growth Differentiation Factor 11 (GDF11) has demonstrated anti-injury and Anti-aging abilities in certain tissues; however, its regulatory role in OA remains unclear and requires further investigation.

Objectives: To identify whether GDF11 can attenuate osteoarthritis. To exploring the the potential mechanism of GDF11 in alleviating osteoarthritis.

Methods: In this study, we cultured and stimulated mouse primary chondrocytes with or without TNF-α, analyzing the resulting damage phenotype through microarray analysis. Additionally, we employed GDF11 conditional knockout mice OA model to examine the relationship between GDF11 and OA. To investigate the target of GDF11's function, we utilized NLRP3 knockout mice and its inhibitor to verify the potential involvement of the NLRP3 inflammasome.

Results: Our in vitro experiments demonstrated that endogenous overexpression of GDF11 significantly inhibited TNF-α-induced cartilage matrix degradation and inflammatory expression in chondrocytes. Furthermore, loss of GDF11 led to NLRP3 inflammasome activation, inflammation, and metabolic dysfunction. In an in vivo surgically induced mouse model, intraarticular administration of recombinant human GDF11 alleviated OA pathogenesis, whereas GDF11 conditional knockout reversed this effect. Additionally, findings from the NLRP3-knockout DMM mouse model revealed that GDF11 exerted its protective effect by inhibiting NLRP3.

Conclusion: These findings demonstrate the ability of GDF11 to suppress TNF-α-induced inflammation and cartilage degeneration by preventing mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation, suggesting its potential as a promising therapeutic drug for osteoarthritis.

Keywords

GDF11; NLRP3 inflammasome; Osteoarthritis; TNF-α.

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