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. About 1.3 million total joint implants are placed annually, and around 80,000 patients develop implant failure due to periimplant fibrosis. Here, the authors show that inhibition of GREM1 in LEPR⁺ cells reduces peri-implant fibrosis and enhances per-implant osteogenesis, therefore represent a promising strategy to prevent and treat aseptic loosening.
Suhardi et al. (Mon,) studied this question.