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TGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice

Author

Listed:
  • Jinbo Li

    (University of Rochester Medical Center
    Hebei Medical University)

  • Zhenqiang Yao

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Xin Liu

    (Tianjin Hospital)

  • Rong Duan

    (University of Rochester Medical Center)

  • Xiangjiao Yi

    (The First Affiliated Hospital of Anhui University of Chinese Medicine)

  • Akram Ayoub

    (University of Rochester Medical Center
    Leica Biosystems)

  • James O. Sanders

    (University of Rochester Medical Center
    University of North Carolina)

  • Addisu Mesfin

    (University of Rochester Medical Center)

  • Lianping Xing

    (University of Rochester Medical Center
    University of Rochester Medical Center)

  • Brendan F. Boyce

    (University of Rochester Medical Center
    University of Rochester Medical Center
    University of Rochester Medical Center)

Abstract

TGFβ1 induces age-related bone loss by promoting degradation of TNF receptor-associated factor 3 (TRAF3), levels of which decrease in murine and human bone during aging. We report that a subset of neutrophils (TGFβ1+CCR5+) is the major source of TGFβ1 in murine bone. Their numbers are increased in bone marrow (BM) of aged wild-type mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CCL5, suggesting that TRAF3 in MPCs limits TGFβ1+CCR5+ neutrophil numbers in BM of young mice. During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFβ1+CCR5+ neutrophil numbers in BM where they induce bone loss. TGFβ1+CCR5+ neutrophils decreased bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, reduced TGFβ1+CCR5+ neutrophil numbers in BM and increased bone mass in aged mice. 15-mon-old mice with TGFβRII specifically deleted in MPCs had lower numbers of TGFβ1+CCR5+ neutrophils in BM and higher bone volume than wild-type littermates. We propose that pharmacologic reduction of TGFβ1+CCR5+ neutrophil numbers in BM could treat or prevent age-related osteoporosis.

Suggested Citation

  • Jinbo Li & Zhenqiang Yao & Xin Liu & Rong Duan & Xiangjiao Yi & Akram Ayoub & James O. Sanders & Addisu Mesfin & Lianping Xing & Brendan F. Boyce, 2023. "TGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35801-z
    DOI: 10.1038/s41467-023-35801-z
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    1. Xiao L. Chang & Gabriela M. Webb & Helen L. Wu & Justin M. Greene & Shaheed Abdulhaqq & Katherine B. Bateman & Jason S. Reed & Cleiton Pessoa & Whitney C. Weber & Nicholas Maier & Glen M. Chew & Roxan, 2021. "Antibody-based CCR5 blockade protects Macaques from mucosal SHIV transmission," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Ji-Won Lee & Akiyoshi Hoshino & Kazuki Inoue & Takashi Saitou & Shunsuke Uehara & Yasuhiro Kobayashi & Satoshi Ueha & Kouji Matsushima & Akira Yamaguchi & Yuuki Imai & Tadahiro Iimura, 2017. "The HIV co-receptor CCR5 regulates osteoclast function," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
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    1. Jiaoling Chen & Yaxing Bai & Ke Xue & Zhiguo Li & Zhenlai Zhu & Qingyang Li & Chen Yu & Bing Li & Shengxian Shen & Pei Qiao & Caixia Li & Yixin Luo & Hongjiang Qiao & Erle Dang & Wen Yin & Johann E. G, 2023. "CREB1-driven CXCR4hi neutrophils promote skin inflammation in mouse models and human patients," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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