1. Academic Validation
  2. FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis

  • Bone Res. 2022 Jun 22;10(1):45. doi: 10.1038/s41413-022-00211-2.
Dong Guo  # 1 2 3 4 Chuangxin Lin  # 5 Yuheng Lu  # 1 2 3 4 Hong Guan 1 2 3 4 Weizhong Qi 1 2 3 4 Hongbo Zhang 1 2 3 4 Yan Shao 1 2 3 4 Chun Zeng 1 2 3 4 Rongkai Zhang 1 2 3 4 Haiyan Zhang 6 7 8 9 Xiaochun Bai 10 11 Daozhang Cai 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Joint Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 2 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 3 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China.
  • 5 Department of Orthopedic Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China.
  • 6 Department of Joint Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 7 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 8 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. zhhy0704@126.com.
  • 9 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. zhhy0704@126.com.
  • 10 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. baixc15@smu.edu.cn.
  • 11 State Key Laboratory of Organ Failure Research, Department of Cell Biology, Southern Medical University School of Basic Medical Sciences, Guangzhou, China. baixc15@smu.edu.cn.
  • 12 Department of Joint Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 13 Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 14 The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China. cdz@smu.edu.cn.
  • 15 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China. cdz@smu.edu.cn.
  • # Contributed equally.
Abstract

Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis (RA). Fatty acid-binding protein 4 (FABP4), a novel adipokine that regulates inflammation and angiogenesis, has been extensively studied in a variety of organs and diseases. However, the effect of FABP4 on RA remains unclear. Here, we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA. The increase in FABP4 promoted synovitis, angiogenesis, and cartilage degradation to exacerbate RA progression in vivo and in vitro, whereas BMS309403 (a FABP4 inhibitor) and anagliptin (Dipeptidyl Peptidase 4 inhibitor) inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression. Further studies showed that constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice. In contrast, inhibition of mTORC1 by Ras homolog enriched in brain (Rheb1) disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice. Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis, angiogenesis, and cartilage degradation in RA. BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development. Hence, FABP4 may represent a potential target for RA therapy.

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