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<p>Globally, approximately 1.3 million total joint implants are placed annually, and around 80,000 patients develop aseptic loosening, a leading cause of implant failure driven by peri-implant fibrosis. Here, we show that the BMP-antagonist Gremlin-1 (GREM1), expressed by leptin receptor–expressing skeletal (LEPR⁺) cells, is a key regulator of this process. GREM1 is highly expressed by LEPR⁺ cells in peri-implant fibrotic tissue in mice and humans. Conditional deletion of <i>Grem1</i> in LEPR⁺ cells attenuate peri-implant fibrosis and enhances peri-implant osteogenesis. Transcriptomic and functional analyses show that loss of <i>Grem1</i> in LEPR⁺ cells upregulate the bone morphogenetic protein (BMP) and WNT pathways, increasing in vivo osteogenesis and reducing fibrous tissue formation. As proof-of-concept, intra-articular administration of a neutralizing antibody against GREM1 (anti-GREM1) in mice prevents and reverses peri-implant fibrous tissue while promoting peri-implant bone formation. Inhibition of GREM1 in LEPR⁺ cells therefore represent a promising strategy to prevent and treat aseptic loosening.</p>

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GREM1 acts in leptin receptor-expressing skeletal cells to mediate peri-implant fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Vincentius Jeremy Suhardi,
  • Anastasia Oktarina,
  • Yingzhen Niu,
  • Andrew L. Thomson,
  • Jϋrgen Alphonsus,
  • Nicolas Suhardi,
  • Jason McCormick,
  • Ugur Ayturk,
  • Matthew B. Greenblatt,
  • Lionel B. Ivashkiv,
  • Mathias P. G. Bostrom,
  • Xu Yang

摘要

Globally, approximately 1.3 million total joint implants are placed annually, and around 80,000 patients develop aseptic loosening, a leading cause of implant failure driven by peri-implant fibrosis. Here, we show that the BMP-antagonist Gremlin-1 (GREM1), expressed by leptin receptor–expressing skeletal (LEPR⁺) cells, is a key regulator of this process. GREM1 is highly expressed by LEPR⁺ cells in peri-implant fibrotic tissue in mice and humans. Conditional deletion of Grem1 in LEPR⁺ cells attenuate peri-implant fibrosis and enhances peri-implant osteogenesis. Transcriptomic and functional analyses show that loss of Grem1 in LEPR⁺ cells upregulate the bone morphogenetic protein (BMP) and WNT pathways, increasing in vivo osteogenesis and reducing fibrous tissue formation. As proof-of-concept, intra-articular administration of a neutralizing antibody against GREM1 (anti-GREM1) in mice prevents and reverses peri-implant fibrous tissue while promoting peri-implant bone formation. Inhibition of GREM1 in LEPR⁺ cells therefore represent a promising strategy to prevent and treat aseptic loosening.