CTLA4-Ig sustains osteogenic potential and inhibits osteoclastogenesis in Staphylococcus aureus osteomyelitis.

Abstract

Osteomyelitis (OM) is a severe bone-destructive disease characterized by infection and inflammation. Transcriptomic analysis of datasets GSE18043 and GSE30119 identified CTLA4 as a key regulator associated with immune modulation and osteogenic differentiation. Subsequent bioinformatic and immune infiltration analyses revealed that CTLA4 expression correlated with increased anti-inflammatory macrophage infiltration and activation of the Wnt/β-catenin signaling pathway of osteoblasts. Functionally, CTLA4-Ig promoted osteogenic differentiation, enhanced matrix mineralization, and upregulated osteogenic markers in MC3T3-E1 cells, while concurrently inhibiting osteoclast formation and bone resorption activity. In a Staphylococcus aureus-induced rat OM model, histological and immunohistochemical analyses further confirmed enhanced osteoblast activity and reduced osteoclast presence in the CTLA4-Ig treated group. CTLA4-Ig administration preserved bone structural integrity by modulating the inflammatory microenvironment, characterized by reduced expression of pro-inflammatory cytokines, increased levels of anti-inflammatory cytokines, enhanced osteogenic regeneration, and a reduction in bacterial burden. Collectively, these findings established CTLA4-Ig as a dual-action modulator that promoted bone regeneration while inhibiting bone destruction, offering a promising therapeutic strategy for OM.