2. Academic Validation
  3. IL-33-Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1-IGF2R Axis in Ankylosing Spondylitis

IL-33-Induced TREM2+ Macrophages Promote Pathological New Bone Formation Through CREG1-IGF2R Axis in Ankylosing Spondylitis

  • Adv Sci (Weinh). 2025 May;12(18):e2500952. doi: 10.1002/advs.202500952.
Wenjun Hao 1 2,  Siwen Chen 1 2,  Hua Chao 1 2,  Zihao Li 1 2,  Hao Yang 3,  Dongying Chen 4,  Sifang Li 1 2,  Shuai Zhang 1 2,  Jingyu Zhang 1 2,  Jianru Wang 1 2,  Zemin Li 1 2,  Xiang Li 1 2,  Zhongping Zhan 4,  Tangming Guan 5,  Yiwen Zhang 6,  Wende Li 5,  Hui Liu 1 2
Affiliations

Affiliations

  • 1 Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 2 Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, 510080, China.
  • 3 Pediatric Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 102200, China.
  • 4 Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
  • 5 Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals, Guangzhou, 510000, China.
  • 6 Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
PMID: 40091508 DOI: 10.1002/advs.202500952
Abstract

Pathological new bone formation is the main cause of disability in ankylosing spondylitis (AS), and so far, it lacks a targeted therapy. Macrophages are central orchestrators of inflammation progression and tissue remodeling, but their contribution to pathological new bone formation has largely not been explored. Here, it is identified that TREM2+ macrophages predominated within the sites of new bone formation and adjacent to osteogenic precursor cells. In vivo, both depletion of macrophages and knockout of Trem2 significantly reduced pathological new bone formation in a Collagen antibody-induced arthritis (CAIA) model. Specifically, TREM2+ macrophages promoted osteogenic differentiation of ligament-derived progenitor cells (LDPCs) by secreting CREG1, a secretory glycoprotein involved in cell differentiation and normal physiology. CREG1-IGF2R-PI3K-AKT signaling pathway is involved in TREM2+ macrophage-mediated pathological new bone formation. In addition, it is found that IL-33 promoted TREM2+ macrophage differentiation through phosphorylation of STAT6. Targeting the above signalings alleviated new bone formation in the CAIA model. The findings highlight the critical role of IL-33-induced TREM2+ macrophages in pathological new bone formation and provide potential therapeutic targets for halting spinal ankylosis in AS.

Keywords

CREG1; IL33; TREM2+ macrophages; ankylosing spondylitis; pathological new bone formation.

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