Pro-osteogenic implants inhibit local excessive B cell maturation via neutrophils-derived CD52 signaling to enhance osseointegration.

Abstract

Metallic implants have been widely utilized in orthopedics surgery. Osseointegration is a local tradeoff between the inflammatory microenvironment and repair processes surrounding implants, driven by innate and adaptive immune cells. B cells contribute to bone metabolism during fracture healing and in several bone-destructive diseases, such as rheumatoid arthritis and periodontitis. However, the participation of B cells in implantable biomaterials-mediated osseointegration has not been extensively studied, even though they occupy a significant proportion at the injury site. Here, we characterized the heterogeneity of immune cells surrounding bone implants and identified the crucial role of infiltrating B cells based on the implantation model in murine tibias via single-cell RNA sequencing (scRNA-seq). Excessive B cell maturation was observed around implants with poor bone formation, compared with pro-osteogenic implants. Additionally, targeting mature B cells via anti-CD20 depletion antibody restored the damaged osseointegration. Differential expression genes analysis and the application of neutralizing antibodies demonstrated that up-regulated Tnfa and Il1b in B cell maturation attenuated the osteogenic differentiation of bone marrow mesenchymal stromal cells (BMSCs). In terms of potential mechanisms, we discovered that pro-osteogenic implants indirectly suppressed local B cell maturation through neutrophils-derived CD52-SiglecG axis, inhibiting downstream ERK1/2 and NF-κB signaling pathways. In summary, our study underscores the pivotal role of B cells in osseointegration and offers novel insights into a promising therapeutic avenue for developing bone biomaterials with immunomodulatory properties and promoting peri-implant bone regeneration.