Bioactive glass-induced B cell depletion remodels the osteoimmunological microenvironment to enhance osteogenesis

Abstract

B cells are critical in bone homeostasis, and their dysfunction is linked to various bone disorders. Bioactive glasses (BGs) are known for their immunomodulatory properties and are increasingly utilized in bone regeneration. However, the specific effects of BGs on B cells and their subsequent impact on osteogenesis remain unclear. In this study, we investigated the immunomodulatory effects of three BGs (45S5-BG, 13-93-BG, and B3-Cu-Zn-BG) on B cells. 13-93-BG had minimal effect on the survival of activated B cells, while 45S5-BG induced a noticeable cytotoxic effect on B cells. Notably, B3-Cu-Zn-BG exhibited the highest cytotoxicity towards pathogenic B cells, prompting further investigation into its mechanisms. The ionic dissolution products (IDPs) of B3-Cu-Zn-BG exerted concentration- and time-dependent cytotoxicity on B cells by upregulating the expression of genes associated with the mitochondrial apoptosis pathway and NADPH oxidases. B3-Cu-Zn-BG-derived IDPs elevated reactive oxygen species production in B cells, which induced apoptosis in a concentration-dependent manner. Additionally, when co-cultured with bone marrow stem cells (BMSCs), B3-Cu-Zn-BG-derived IDPs promoted osteoblastic differentiation of BMSCs while selectively targeting and eliminating B cells. To confirm the in vivo osteoimmunomodulatory effects of B3-Cu-Zn-BG-derived IDPs, we employed a human tumor necrosis factor transgenic (TNF-tg) mouse model of rheumatoid arthritis. Intra-articular injection of the IDPs in TNF-tg arthritic mice attenuated bone erosion by reducing B cell aggregates and improving osteoblastic differentiation. This study indicates that B3-Cu-Zn-BG not only induces B cell apoptosis but also promotes osteogenesis, highlighting its potential as a therapeutic strategy for inflammatory bone diseases. STATEMENT OF SIGNIFICANCE: Despite decades of use in tissue regeneration, bioactive glasses (BGs) have not been thoroughly evaluated for their immunomodulatory effects. B cells play a crucial role in the pathogenesis of numerous inflammatory bone diseases. By investigating the immunomodulatory properties of B3-Cu-Zn-BG, this research reveals its ability to selectively induce B cell apoptosis and promote osteoblastic differentiation of bone marrow stem cells. Notably, in a rheumatoid arthritis mouse model, B3-Cu-Zn-BG significantly reduced bone erosion and enhanced osteogenesis. BGs of specific compositions have thus great potential in regulating the osteoimmunology microenvironment by locally modulating B cells. These findings underscore the potential of BGs as a novel therapeutic approach for inflammatory bone diseases, offering insights into bone regeneration and immunomodulation.

Keywords: B cells; Bioactive glass; Bone marrow stem cells; Immunomodulation; Selective cytotoxicity.