Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-codingHLA-DRB1allele

Abstract

ObjectiveShared epitope (SE)-coding DRB1 alleles are associated with bone erosion in several diseases, including rheumatoid arthritis (RA) and periodontal disease (PD), but the underlying mechanism is unknown. We have recently identified the SE as an osteoclast-activating ligand. To better understand the biological effects of the SE in vivo, here we sought to determine whether it can facilitate spontaneous bone damage in naïve mice.Methods3-month old naïve transgenic mice that carry the human SE-coding allele DRB1*04:01, or a SE-negative allele DRB1*04:02 were studied. Bone tissues were analysed by micro-CT, and the tooth-supporting tissues were studied by histology, immunohistochemistry and immunofluorescence. Serum biomarkers were determined by ELISA.ResultsTransgenic mice expressing the SE-coding DRB1*04:01 allele, but not mice carrying the SE-negative allele DRB1*04:02, showed spontaneous PD associated with interleukin (IL)-17 overabundance and periostin disruption. Mandibular bone volumetric and mineralisation parameters were significantly lower in SE-positive mice, and alveolar bone resorption was significantly increased in these mice. SE-positive mice also had more slender tibiae, and their marrow, cortical and total areas were lower than those of SE-negative mice. Additionally, significantly increased serum IL-17, tumour necrosis factor-α and osteoprotegrin levels were found in SE-positive mice, while their receptor activator of nuclear factor κ-B ligand levels were significantly lower.ConclusionsA human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases.

Linkage of Periodontitis and Rheumatoid Arthritis: Current Evidence and Potential Biological Interactions

“…It is possible that some common genetic traits are associated with increased susceptibility to these conditions. One potential genetic influence connecting RA and PD is the shared epitope (SE)-coding HLA-DRB1 allele [112]. According to van der Woude et al [113] 50% of the risk to develop RA is attributed to genetic factors, and the most relevant genetic association in RA is with the SE-coding HLA-DRB1 gene that confers more than 80% of susceptibility for joint destruction [64,114].…”

“…The SE-coding DRB1 alleles have been associated with bone erosions in RA as well as alveolar bone destruction during PD progression [118,119,120]. Recent data [112] shows that the transgenic mice carrying a human SE-coding HLA-DRB1 allele present spontaneous alveolar bone resorption and osteopenic skeletal changes, characterized by slenderer tibiae and decreased total bone area in the marrow and cortical tibial bones. Furthermore, overexpression of pro-inflammatory cytokines IL-17 and TNF-α were also found in SE-positive mice.…”

Periodontitis and Rheumatoid Arthritis: The Same Inflammatory Mediators?

“…The possible role of SE-coding DRB1 alleles has been recently underlined by Gehlot and colleagues: the authors observed that transgenic SE+ mice, but not SE- mice, spontaneously developed PD, associated with IL17 overexpression and periostin disruption. Moreover, SE-positive mice showed significantly lower mandibular bone volumetric and mineralization parameters, together with increased alveolar bone resorption [34].…”

“…Data from literature provides some evidences to support the association between an aggressive PD and SNPs in interleukin 1 beta (IL1 β ), interleukin 1 receptor antagonist (IL1RN), FCGR IIIb, vitamin D receptor (VDR), and Toll-like receptor 4 (TLR4) genes. Moreover, a chronic PD was associated with polymorphisms in IL1B, IL1RN, IL6, IL10, VDR, CD14, TLR4, and matrix metalloproteinase-1 (MMP1) genes [34]. The low statistical power of these studies was also demonstrated by the results of the meta-analysis conducted by Nikolopoulos and colleagues in 2008, confirming exclusively a moderate and weak positive association between the IL1 composite and IL1B-511 genotypes and the occurrence of chronic PD [36].…”

Antigen Presentation-Independent Reciprocal Immune Modulation byHLA-DRB1Allelic Epitopes that Associate with Autoimmune Disease Risk or Protection

“…SE-coding HLA-DRB1 alleles have also been found to associate with type 1 diabetes, autoimmune hepatitis, polymyalgia rheumatica, and temporal arteritis 11,12,13,14 , among other conditions. Additionally, the SE has been found to be a risk factor for erosive bone damage in nosologically-distinct conditions, such as periodontal disease, systemic lupus erythematosus and psoriatic arthritis 15,16,17,18,19 .…”