Lipopolysaccharide Impedes Bone Repair in FcγRIIB-Deficient Mice

Chronic inflammation contributes to the development of skeletal disorders in patients with systemic lupus erythematosus (SLE). Activation of the host immune response stimulates osteoclast activity, which in turn leads to bone loss. Regenerating bone in the inflammatory microenvironments of SLE patients with critical bone defects remains a great challenge. In this study, we utilized lipopolysaccharide (LPS) to imitate locally and systemically pathogenic bacterial infection and examined the bone regeneration performance of LPS-associated mandibular and tibial bone regeneration impairment in FcγRIIB mice. Our results indicated that a loss of FcγRIIB alleviates bone regeneration in both mandibles and tibiae. After LPS induction, FcγRIIB mice were susceptible to impaired fracture healing in tibial and mandibular bones. LPS decreased the mineralization to collagen ratio in FcγRIIB mice, indicating a mineralization defect during bone repair. An osteoblast-associated gene (Col1a1) was attenuated in FcγRIIB-deficient mice, whereas Bglap, Hhip, and Creb5 were further downregulated with LPS treatment in FcγRIIB mice compared to FcγRIIB mice. Alpl and Bglap expression was dcreased in osteoblasts derived from bone chips. An osteoclast-associated gene, Tnfsf11/Tnfrsf11 ratio, ewas increased in LPS-induced FcγRIIB mice and in vitro. Furthermore, systemic LPS was relatively potent in stimulating production of pro-inflammatory cytokines including TNF-α, IL-6, and MCP-1 in FcγRIIB mice compared to FcγRIIB mice. The levels of TNF-α, IFN-β, IL-1α, and IL-17A were increased, whereas IL-10 and IL-23 were decreased in FcγRIIB^-/- mice treated locally with LPS. These findings suggest that both local and systemic LPS burden can exacerbate bone regeneration impairment, delay mineralization and skeletal repair, and induce inflammation in SLE patients.