Lipopolysaccharide Impedes Bone Repair in FcRIIB-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 Fc gamma RIIB-/- mice. Our results indicated that a loss of Fc gamma RIIB alleviates bone regeneration in both mandibles and tibiae. After LPS induction, Fc gamma RIIB-/- mice were susceptible to impaired fracture healing in tibial and mandibular bones. LPS decreased the mineralization to collagen ratio in Fc gamma RIIB-/- mice, indicating a mineralization defect during bone repair. An osteoblast-associated gene (Col1a1) was attenuated in Fc gamma RIIB-deficient mice, whereas Bglap, Hhip, and Creb5 were further downregulated with LPS treatment in Fc gamma RIIB-/- mice compared to Fc gamma RIIB-/- 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 Fc gamma RIIB-/- mice and in vitro. Furthermore, systemic LPS was relatively potent in stimulating production of pro-inflammatory cytokines including TNF-alpha, IL-6, and MCP-1 in Fc gamma RIIB-/- mice compared to Fc gamma RIIB-/- mice. The levels of TNF-alpha, IFN-beta, IL-1 alpha, and IL-17A were increased, whereas IL-10 and IL-23 were decreased in Fc gamma RIIB-/- 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.