Genome-Wide Association Study Identifies CXCR3 as a Partial Mediator of LPS-induced Periodontitis

Periodontitis (PD) is characterized by bacterial infection and inflammation of supporting tissues of the teeth. If left untreated, PD can lead to tooth loss. PD affects ~47% of the U.S. population over 30 and, interestingly, twin studies have shown PD to be 50% heritable. While the host immunoinflammatory response and genetic background play a role in PD, few studies have mechanistically interrogated genetic targets to validate candidate genes associated with PD.Objective: Identify genes that mediate Lipopolysaccharide (LPS)-induced periodontitis.Methods: P. gingivalis (P.g.)-LPS was injected between maxillary molars in 104 strains of the Hybrid Mouse Diversity Panel (HMDP) 2x/week for 6 weeks. Following sacrifice, maxillae were scanned (microCT) and bone loss was quantitated. FaST-LMM was used to identify genetic loci associated to bone loss. Gene expression (microarray) and protein (histology) were further assessed in A/J and C57BL/6J. CX-C motif chemokine receptor 3 (CXCR3) knockout (KO) and wild-type (WT) mice were analyzed radiographically and histologically after LPS-injections. AMG-487, an in vivo CXCR3 inhibitor, was injected systemically and locally and maxillae were analyzed radiographically and histologically after LPS-injections to investigate the therapeutic potential of CXCR3 inhibition.Results: 50% heritability and a strain-dependent 6-fold difference in LPS-induced bone loss were observed across the HMDP. Our FaST-LMM and RNA expression data identified Cxcl family members (inflammatory immune cell chemoattractants essential in immune responses) as associated with PD. Additionally, Cxcl10 protein, as well as, an increase in immune cells and pro-inflammatory cytokines were observed in C57BL/6J (high bone loss) and not in A/J (low bone loss) after LPS-injections. Most interestingly, deleting CXCR3 (Cxcl10 receptor), demonstrated ~50% reduction in bone loss and a decrease in osteoclasts after LPS-injections compared to WT mice. Furthermore, mice treated with AMG-487 systemically and locally resulted in ~50% reduction in bone loss and decreased osteoclasts after LPS-injections.Conclusions: Using a genome-wide association approach, we have identified CXCR3 as a possible target for modulating the host response in PD susceptibility. Our future work will characterize the CXCR3 pathway and validate other candidate genes associated with LPS-induced bone loss with the ultimate goal to identify patients at high risk to PD