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

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.