Therapeutic targeting of cathepsin C::from pathophysiology to treatment

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects of inflammatory/auto-immune disorders mediated by these proteases. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome. The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials

Studies on clinical expression, genotype, and gingival crevicular fluid characteristics in young patients with Papillon-Lefèvre syndrome

Papillon-Lefèvre syndrome (PLS) is an autosomal recessive condition with palmoplantar hyperkeratosis and aggressive periodontitis as cardinal features. The disorder is linked to mutations of the gene for cathepsin C, a lysosomal protease essential in activation of serine proteases in immune and inflammatory cells. The genetic background of the disorder has been identified, but its relation to phenotypic expression is obscure. The aims of the project were to explore phenotypic expression in young patients with PLS, and to investigate any correlation between clinical expression and identified genotype. Additionally, biochemical properties of gingival crevicular fluid (GCF) were investigated, and the result of an oral treatment protocol based on plaque control was evaluated. Major results and conclusions from the studies were: The severity of the skin lesions showed no correlation to patient’s age or level of periodontal disease, supporting the concept that the two major components of PLS are independent of each other. Genotyping revealed two cardinal genotypes, but no correlation between the identified genotypes and expression of phenotypes could be found, suggesting that it is the interaction with environmental factors and/or other genes that is important in shaping the phenotype. Analyses of gingival crevicular fluid (GCF) from patients with PLS did not show any clear-cut pathognominic expressions with regard to content of cytokines, metalloproteinases or inhibitor of metallproteinase 1. The level of plasminogen activator inhibitor in GCF was significantly higher in PLS patients than in controls, indicating atypical activity of the plasminogen activating system with, possibly, disturbed epithelial function. This may affect the epithelial barrier function and its role in the innate defence system. Evaluation of a PLS oral treatment protocol showed treatment from an early age and compliance to the program to be important in preserving permanent teeth in PLS

Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls

Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls, 2015, BMC Oral Health, Abstract Background: Previous studies have suggested that children with oral clefts may have higher caries prevalence in comparison with non-cleft controls but the relative importance of the potential risk factors is not clear. The aim of this study was to compare the caries risk profiles in a group of cleft lip and/or palate (CL(P)) children with non-cleft controls in the same age using a computerized caries risk assessment model. Methods: The study group consisted of 133 children with CL(P) (77 subjects aged 5 years and 56 aged 10 years) and 297 non-cleft controls (133 aged 5 years and 164 aged 10 years). A questionnaire was used to collect data concerning the child's oral hygiene routines, dietary habits and fluoride exposure. Oral hygiene was assessed using Quigley-Hein plaque Index and the caries prevalence and frequency was scored according to the International Caries Detection and Assessment System. Whole saliva samples were analyzed for mutans streptococci, lactobacilli, buffering capacity and secretion rate. The risk factors and risk profiles were compared between the groups with aid of Cariogram and the estimated risk for future caries was categorized as "high" or "low". Results: Children with CL(P) (the entire study group) had significantly higher counts of salivary lactobacilli (p < 0.05) and displayed less good oral hygiene (p < 0.05). More 10-year-old children in the CL(P) group had low secretion rate but this difference was not significant. The average chance to avoid caries ranged from 59 to 67 % but there were no significant differences between the groups. The odds of being categorized with high caries risk in the CL(P) group was significantly elevated (OR = 1.89; 95 % CI = 1.25-2.86). In both groups, children in the high risk category had a higher caries experience than those with low risk. Conclusion: Children with CL(P) displayed increased odds of being categorized at high caries risk with impaired oral hygiene and elevated salivary lactobacilli counts as most influential factors. The results suggest that a caries risk assessment model should be applied in the routine CL(P) care as a basis for the clinical decision-making and implementation of primary and secondary caries prevention

Tissue Plasminogen Activator (t-PA) and Placental Plasminogen Activator Inhibitor (PAI-2) in Gingival Crevicular Fluid from Pa-tients with Papillon-Lefevre Syndrome

OBJECTIVES: Numerous patients with Papillon-Lefevre syndrome (PLS) express a severe periodontal inflammation that results in prema-ture loss of deciduous and permanent teeth. The plasminogen activat-ing (PA) system is involved in physiological and pathological processes including epithelial healing, extracellular proteolysis and local in-flammatory reactions. The aim of the study was to explore a possible role of the PA system in patients with PLS. MATERIAL AND METHODS: Samples of gingival crevicular fluid (GCF) were collected from areas with gingival infection in 20 patients with PLS and in 20 healthy controls. The concentration of tissue plasminogen activator (t-PA) and inhibitor (PAI-2) was measured with ELISA. RESULTS: The median level of PAI-2 was significantly higher (p < 0.01) in PLS pa-tients than in the controls, while the median value of t-PA did not dif-fer between the groups. No difference in t-PA or PAI-2 levels was found regarding age, gender or presence of active periodontal disease. CONCLUSION: The findings indicate an atypical activity of the PA system with a disturbed epithelial function in PLS patients, suggesting that the periodontal destruction seen in patients with PLS is secondary to a hereditary defect in the defense system

Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls

Background: Previous studies have suggested that children with oral clefts may have higher caries prevalence in comparison with non-cleft controls but the relative importance of the potential risk factors is not clear. The aim of this study was to compare the caries risk profiles in a group of cleft lip and/or palate (CL(P)) children with non-cleft controls in the same age using a computerized caries risk assessment model. Methods: The study group consisted of 133 children with CL(P) (77 subjects aged 5 years and 56 aged 10 years) and 297 non-cleft controls (133 aged 5 years and 164 aged 10 years). A questionnaire was used to collect data concerning the childs oral hygiene routines, dietary habits and fluoride exposure. Oral hygiene was assessed using Quigley-Hein plaque Index and the caries prevalence and frequency was scored according to the International Caries Detection and Assessment System. Whole saliva samples were analyzed for mutans streptococci, lactobacilli, buffering capacity and secretion rate. The risk factors and risk profiles were compared between the groups with aid of Cariogram and the estimated risk for future caries was categorized as "high" or "low". Results: Children with CL(P) (the entire study group) had significantly higher counts of salivary lactobacilli (p less than 0.05) and displayed less good oral hygiene (p less than 0.05). More 10-year-old children in the CL(P) group had low secretion rate but this difference was not significant. The average chance to avoid caries ranged from 59 to 67 % but there were no significant differences between the groups. The odds of being categorized with high caries risk in the CL(P) group was significantly elevated (OR = 1.89; 95 % CI = 1.25-2.86). In both groups, children in the high risk category had a higher caries experience than those with low risk. Conclusion: Children with CL(P) displayed increased odds of being categorized at high caries risk with impaired oral hygiene and elevated salivary lactobacilli counts as most influential factors. The results suggest that a caries risk assessment model should be applied in the routine CL(P) care as a basis for the clinical decision-making and implementation of primary and secondary caries prevention.Funding Agencies|FORSS - Medical Research Council of Southeast Sweden, Futurum, - Academy of Health and Care Jonkoping County Council; Swedish Dental Association; Swedish Society of Paediatric Dentistry</p

Comparing caries risk profiles between 5-and 10-year-old children with cleft lip and/or palate and non-cleft controls

Background: Previous studies have suggested that children with oral clefts may have higher caries prevalence in comparison with non-cleft controls but the relative importance of the potential risk factors is not clear. The aim of this study was to compare the caries risk profiles in a group of cleft lip and/or palate (CL(P)) children with non-cleft controls in the same age using a computerized caries risk assessment model. Methods: The study group consisted of 133 children with CL(P) (77 subjects aged 5 years and 56 aged 10 years) and 297 non-cleft controls (133 aged 5 years and 164 aged 10 years). A questionnaire was used to collect data concerning the childs oral hygiene routines, dietary habits and fluoride exposure. Oral hygiene was assessed using Quigley-Hein plaque Index and the caries prevalence and frequency was scored according to the International Caries Detection and Assessment System. Whole saliva samples were analyzed for mutans streptococci, lactobacilli, buffering capacity and secretion rate. The risk factors and risk profiles were compared between the groups with aid of Cariogram and the estimated risk for future caries was categorized as "high" or "low". Results: Children with CL(P) (the entire study group) had significantly higher counts of salivary lactobacilli (p less than 0.05) and displayed less good oral hygiene (p less than 0.05). More 10-year-old children in the CL(P) group had low secretion rate but this difference was not significant. The average chance to avoid caries ranged from 59 to 67 % but there were no significant differences between the groups. The odds of being categorized with high caries risk in the CL(P) group was significantly elevated (OR = 1.89; 95 % CI = 1.25-2.86). In both groups, children in the high risk category had a higher caries experience than those with low risk. Conclusion: Children with CL(P) displayed increased odds of being categorized at high caries risk with impaired oral hygiene and elevated salivary lactobacilli counts as most influential factors. The results suggest that a caries risk assessment model should be applied in the routine CL(P) care as a basis for the clinical decision-making and implementation of primary and secondary caries prevention.Funding Agencies|FORSS - Medical Research Council of Southeast Sweden, Futurum, - Academy of Health and Care Jonkoping County Council; Swedish Dental Association; Swedish Society of Paediatric Dentistry</p

Papillon-Lefevre syndrome: report of six patients and identification of a novel mutation

Papillon-Lefevre syndrome is an autosomal recessive genodermatosis typically manifesting with the constellation of palmoplantar keratoderma and progressive early-onset periodontitis. The cutaneous phenotype can be strikingly psoriasiform, possibly posing a diagnostic challenge. This rare disorder is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. We report six patients with Papillon-Lefevre syndrome from five consanguineous Turkish families, in whom genetic analysis of the CTSC gene revealed four recurrent mutations (c.415G>A; c.1015C>T; c.1019A>G; and c.103-105delCTG) and a novel missense mutation (c.117G>T) in the homozygous state