2. Academic Validation
  3. Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation

Hyperglycemia exacerbates osteoarthritis by impairing macrophage efferocytosis through modulation of CD11b lactylation

  • Nat Commun. 2025 Dec 12. doi: 10.1038/s41467-025-67473-2.
Hao Zhou # 1,  Yong Xiao # 2,  Xinchen Xue # 1,  Jiuxiang Liu # 1,  Hongtao Xu 1,  Jinwen Wang 1,  Jinchun Zhou 1,  Qiang Zuo 1,  Wenwei Liang 1,  Huanghe Song 1,  Zhefeng Chen 1,  Feng Liu 1,  Xiao Li 3 4,  Kai Shen 5,  Weimin Fan 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Department of Orthopaedics, Xinjiang Production and Construction Corps Fourth Division Hospital, Ili, Xinjiang, China.
  • 3 Department of Radiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China. [email protected].
  • 4 Department of Radiology, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • 5 Department of Orthopaedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • 6 Department of Orthopaedics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 41387463 DOI: 10.1038/s41467-025-67473-2
Abstract

Osteoarthritis (OA) and diabetes predominantly affect middle-aged and elderly populations, with OA patients frequently presenting with comorbid diabetes. Despite evidence that diabetes aggravates OA progression, the underlying mechanisms are not fully understood. Here, we demonstrate that hyperglycaemia exacerbates OA progression through CD11b lactylation-mediated impairment of macrophage efferocytosis. Mechanistically, hyperglycemia enhances glycolysis in synovial macrophages, leading to lactate accumulation and CD11b lactylation at K575. This post-translational modification alters the conformation of the CD11b protein, impairing recognition of apoptotic cells and compromising synovial macrophage efferocytosis, thereby exacerbating inflammation and accelerating OA progression. Additionally, we identify CBP as a lactyl-transferase whose targeted knockdown in synovial macrophages effectively reduces lactylation levels, restores efferocytosis function, and delays hyperglycemia-associated OA progression. Collectively, our findings represent an important molecular mechanism by which hyperglycemia aggravates OA and suggest that targeting CBP could be utilized as therapeutic strategy for mitigating hyperglycemia-associated OA.

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