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Targeting Notch‐Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis
Author(s) -
Sun Wen,
Zhang Hengwei,
Wang Hua,
Chiu Yahui Grace,
Wang Mengmeng,
Ritchlin Christopher T,
Kiernan Amy,
Boyce Brendan F,
Xing Lianping
Publication year - 2017
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3117
Subject(s) - hes1 , tumor necrosis factor alpha , green fluorescent protein , arthritis , bone marrow , notch signaling pathway , microbiology and biotechnology , immunology , medicine , chemistry , endocrinology , biology , receptor , biochemistry , gene
Expression levels of Notch signaling molecules are increased in synovium from patients with rheumatoid arthritis (RA). However, it is not known which cell type(s) in RA synovium have Notch activation or if they play a pathogenetic role in RA. Here, we used Hes1 ‐GFP/TNF‐transgenic (TNF‐Tg) mice to investigate the role of cells with active Notch signaling (GFP+) in RA. The number of GFP+ cells was significantly increased in synovium in Hes1 ‐GFP/TNF‐Tg mice and about 60% of them were F4/80+ macrophages expressing the inflammatory macrophage (M1) marker. TNF‐Tg mice transplanted with Hes1 ‐GFP/TNF‐Tg bone marrow (BM) had significantly more GFP+ cells in their synovium than in BM. Intraarticular injection of Hes1 ‐GFP/TNF‐Tg or Hes1 ‐GFP+ BM macrophages into WT and TNF‐Tg mice showed the highest synovial GFP+ cells in the TNF‐Tg mice that received Hes1 ‐GFP/TNF‐Tg cells. Thapsigargin (THAP), a Notch inhibitor, decreased TNF‐induced M1 and increased M2 numbers and reduced joint lesion, synovial M1s, and GFP+ cells in Hes1 ‐GFP/TNF‐Tg mice. THAP did not affect M1s from mice carrying a constitutively active Notch1. Thus, the main cells with activated Notch signaling in the inflamed synovium of TNF‐Tg mice are M1s derived from BM and targeting them may represent a new therapeutic approach for patients with inflammatory arthritis. © 2017 American Society for Bone and Mineral Research.