Genomewide Association Study Identifies Cxcl Family Members as Partial Mediators of LPS-Induced Periodontitis.

Periodontitis (PD) is characterized by bacterial infection and inflammation of tooth-supporting structures and can lead to tooth loss. PD affects ∼47% of the US population over age 30 years and has a heritability of about 50%. Although the host immunoinflammatory response and genetic background play a role, little is known of the underlying genetic factors. We examined natural genetic variation in lipopolysaccharide (LPS)-induced PD across a panel of inbred mouse strains, the hybrid mouse diversity panel (HMDP). We observed a strain-dependent sixfold difference in LPS-induced bone loss across the HMDP with a heritability of 53%. We performed a genomewide association study (GWAS) using FAST-LMM, which corrects for population structure, and identified loci significantly associated with PD. We examined candidate genes at a locus on chromosome 5, which suggested a relationship between LPS-induced bone loss and, together with expression data, identified Cxcl family members as associated with PD. We observed an increase in Cxcl10 protein, as well as immune cells and pro-inflammatory cytokines in C57BL/6J (high bone loss strain) but not in A/J (low bone loss strain) after LPS injections. Genetic deletion of CXCR3 (Cxcl9 and10 receptor) demonstrated a ∼50% reduction in bone loss and reduced osteoclasts after LPS injections. Furthermore, WT mice treated with AMG-487 (a CXCR3 antagonist) showed a ∼45% reduction in bone loss and decreased osteoclasts after LPS injections. We conclude that CXCR3 is a strong candidate for modulating the host response in individuals susceptible to PD. © 2018 American Society for Bone and Mineral Research.

Early intervention of peri-implantitis and periodontitis using a mouse model.

BACKGROUND: Peri-implantitis is an inflammatory response to bacterial biofilm resulting in bone loss and can ultimately lead to implant failure. Because of the lack of predictable treatments available, a thorough understanding of peri-implantitis's pathogenesis is essential. The objective of this study is to evaluate and compare the response of acute induced peri-implantitis and periodontitis lesions after insult removal. METHODS: Implants were placed in one-month-old C57BL/6J male mice eight weeks post extraction of their left maxillary molars. Once osseointegrated, ligatures were placed around the implants and contralateral second molars of the experimental groups. Controls did not receive ligatures. After one week, half of the ligatures were removed, creating the ligature-retained and ligature-removed groups. Mice were sacrificed at two time points, 5 and 14 days, from ligature removal. The specimens were analyzed via micro-computed tomography and histology. RESULTS: By 5 and 14 days after ligature removal, the periodontitis group experienced significant bone gain, whereas the peri-implantitis group did not. Histologically, all implant groups exhibited higher levels of cellular infiltrate than any of the tooth groups. Osteoclast numbers increased in peri-implantitis and periodontitis ligature-retained groups and decreased following insult removal. Collagen was overall more disorganized in peri-implantitis than periodontitis for all groups. Peri-implantitis experimental groups revealed greater matrix metalloproteinase-8 and NF-kB levels than periodontitis. CONCLUSIONS: Implants respond slower and less favorably to insult removal than teeth. Future research is needed to characterize detailed peri-implantitis disease pathophysiology.

Comparing the Healing Potential of Late-Stage Periodontitis and Peri-Implantitis.

Peri-implantitis is defined as an inflammatory disease affecting the tissues around osseointegrated functioning implants. Unfortunately, detailed peri-implantitis pathogenesis is not well understood and current treatments lack predictability. Compare the healing potential of late-stage ligature-induced periodontitis and peri-implantitis after ligature removal. Four-week-old C57BL/6J male mice had their left maxillary molars extracted. After 8 weeks, implants were placed in healed sockets and allowed to osseointegrate. Mice were separated into control (no ligature) and experimental (ligature) groups. In the experimental group, ligatures were placed around the implant and the contralateral second molar. Four weeks later, the ligature group was randomly divided into ligature-retained and ligature-removed groups. Mice were sacrificed at 2 time points: 1 and 2 weeks after ligature removal. The samples were analyzed by microcomputed tomography (micro-CT) and histology. Ligature-induced significant bone loss in peri-implantitis and periodontitis were compared with respective controls. At the 2-week time point, bone formation was observed in the ligature-removed groups compared with respective controls; however, more bone was regained in periodontitis ligature-removed compared with the peri-implantitis ligature-removed group. Histologically, the peri-implantitis ligature-retained group had higher inflammatory levels and a higher number of osteoclasts compared with the periodontitis ligature-retained group. Moreover, in the peri-implantitis ligature-retained group, collagen appeared less organized compared with the periodontitis ligature-retained group at both time points; although collagen tended to reorganize following ligature removal in both conditions. Peri-implantitis does not respond to treatment as well as periodontitis. Future work includes understanding peri-implantitis pathogenesis and developing predictable treatment protocols.