Loricrin and Aggressive Periodontal Disease

Background: Aggressive periodontitis (AgP) is often associated with specific features, such as a unique microbial profile or pattern of host-response (localized to first molars and incisors in some of the cases). Nonetheless, a unifying mechanism has not been established for this condition. AgP patients are typically diagnosed under the age of 35 years and present with plaque accumulation that does not correlate with the degree of bone destruction present. The rapid bone loss ultimately leads to early tooth loss and complex restorative treatment for patients. AgP patients have also been shown to have an increased expression of Th2 cytokines. Although controversial, Th2 cytokines have been observed in the active or “progressive” lesion of chronic periodontal disease. Th2 cytokine expression has been shown to play a role in loricrin downregulation and other studies have shown downregulation of the mRNA for loricrin in AgP patients. Loricrin comprises 70-80% of the total protein mass of the cornified epithelium and its complex cross-linked structure helps maintain the barrier between the external and internal environment. The importance of loricrin as a barrier protein is illustrated in a different inflammatory disease of the skin: atopic dermatitis. Atopic dermatitis patients experience a downregulation of loricrin protein in their skin and as a result, are more susceptible to pathogenic bacteria penetration and a consequential inflammatory response. Research in the area of atopic dermatitis has shown that an increased Th2 response can result in loricrin downregulation via the transcription factor Stat6. As AgP patients exhibit a Th2 response, it is possible that Th2 cytokines activate the Stat6 pathway in AgP patients which leads to downregulation of loricrin in the oral cavity. This downregulation in loricrin could compromise barrier function in the epithelium of patients with AgP and thus, may explain the dramatic inflammatory response they experience. Aims: Aim 1: Determine if downregulation of loricrin at the protein level is associated with AgP in human patients. Aim 2: Determine if Stat6VT mice are a potential model of AgP. Methods: Gingival tissue samples were collected from periodontally healthy patients and AgP patients undergoing routine periodontal surgeries in which tissue is normally discarded, in clinics in Alberta, Canada, and Sao-Paulo, Brazil. Western blot and ELISA techniques were used as loricrin protein detection methods. These methods determined if AgP patients experience a downregulation in loricrin. Loricrin protein concentration was measured in Stat6VT and wild type mice; Stat6VT mice are engineered to overexpress Stat6, and as a result, have higher levels of Th2 cytokines and consequently, loricrin downregulation. ELISA was used to determine any difference in loricrin protein expression in mice oral tissue samples. MicroCT analysis measurements were performed to compare bone loss between the two mouse groups. Sections were obtained and stained with hematoxylin and eosin for histological evaluation. Results: A total of 12 samples from AgP patients and 11 samples from healthy control patients were collected. An ELISA was performed to compare the amount of loricrin protein in the samples. The average concentration of loricrin was significantly higher in the healthy group (9.240±1.572ng/ml) than in the AgP group (2.813±0.8583ng/ml) (p=0.0008, MannWhitney test). A total of 6 Stat6VT mice were compared to 6 wild type mice by ELISA. The difference in loricrin protein expression in the tissue of Stat6VT and wild type mice was not statistically significant (p=0.537) (The means ± S.E. were 0.14 ± 0.03 for wild type and 0.10 ± 0.03 for Stat6). In this first trial, mice were not gender matched, nor scored for dermal lesion severity, which may have affected our outcome. Interestingly however, the Stat6VT mice had significantly more bone loss than wild type mice, even in the absence of specific pathogen challenge. Furthermore, Stat6VT mice showed signs of inflammation and bone resorption in the histological sections. Conclusions: These results suggest that patients with AgP have less loricrin protein expression, consistent with gene expression studies. Based on these results we now hypothesize that decreased loricrin protein may result in a compromised oral barrier by disrupting normal epithelial differentiation, and this may explain why biofilm bacteria cause such a dramatic inflammatory response in AgP patients. Additionally, Stat6VT mice showed increased inflammation and bone resorption compared to wild type. Our results suggest that this mouse strain deserves further study to determine its utility as a model for AgP studies.

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