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

Heparan Sulfate Proteoglycan Modulates Keratinocyte Growth Factor Signaling through Interaction with both Ligand and Receptor

Keratinocyte growth factor (KGF) is an unusual fibroblast growth factor (FGF) family member in that its activity is largely restricted to epithelial cells, and added heparin/heparan sulfate inhibits its activity in most cell types. The effects of heparan sulfate proteoglycan (HSPG) on binding and signaling by acidic FGF (aFGF) and KGF via the KGFR were studied using surface-bound and soluble receptor isoforms expressed in wild type and mutant Chinese hamster ovary (CHO) cells lacking HSPG. Low concentrations of added heparin (1 microgram/mL) enhanced the affinity of ligand binding to surface-bound KGFR in CHO mutants, as well as ligand-stimulated MAP kinase activation and c-fos induction, but had little effect on binding or signaling in wild type CHO cells. Higher heparin concentrations inhibited KGF, but not aFGF, binding and signaling. In addition to the known interaction between HSPG and KGF, we found that the KGFR also bound heparin. The biphasic effect of heparin on KGF, but not aFGF, binding and signaling suggests that occupancy of the HSPG binding site on the KGFR may specifically inhibit KGF signaling. In contrast to events on the cell surface, added heparin was not required for high-affinity soluble KGF-KGFR interaction. These results suggest that high-affinity ligand binding is an intrinsic property of the receptor, and that the difference between the HSPG-dependent ligand binding to receptor on cell surfaces and the HSPG-independent binding to soluble receptor may be due to other molecule(s) present on cell surfaces

Efficacy of bone‐substitute materials use in immediate dental implant placement: A systematic review and meta‐analysis

OBJECTIVE: To assess the efficacy of using a bone substitute material (BSM) in the fixture–socket gap in patients undergoing tooth extraction and immediate implant placement. MATERIALS AND METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for randomized controlled trials (RCTs). RCTs were screened for eligibility, and data were extracted by two authors independently. Risk of bias (ROB) was assessed using Cochrane's ROB tool 2.0. Primary outcomes were implant failure, overall complications, and soft‐tissue esthetics. Secondary outcomes were vertical buccal bone resorption, vertical interproximal bone resorption, horizontal buccal bone resorption, and mid‐buccal mucosal recession. Meta‐analysis was performed using random‐effects model with generic inverse variance weighing. GRADE was used to grade the certainty of the evidence. RESULTS: After screening 19 544 potentially eligible references, 20 RCTs were included in this review, with a total of 848 patients (916 sites). Most included RCTs were deemed of some concerns (53%) or at low (38%) risk of bias, except for overall complications (high ROB). Implant failure did not differ significantly RR = 0.92 (confidence intervals [CI] 0.34 to 2.46) between using a BSM compared with not using a BSM (NoBSM). BSM use resulted in less horizontal buccal bone resorption (MD = −0.52 mm [95% CI −0.74 to −0.30]), a higher esthetic score (MD = 1.49 [95% CI 0.46 to 2.53]), but also more complications (RR = 3.50 [95% CI 1.11 to 11.1] compared with NoBSM. Too few trials compared types of BSMs against each other to allow for pooled analyses. The certainty of the evidence was considered moderate for all outcomes except implant failure (low), overall complications (very low), and vertical interproximal bone resorption (very low). CONCLUSION: BSM use during immediate implant placement reduces horizontal buccal bone resorption and improves the periimplant soft‐tissue esthetics. Although BSM use increases the risk of predominantly minor complications

Successful mandible rehabilitation of lower incisors with one-piece implants

INTRODUCTION: The popularity of one-piece implants has increased considerably among patients and dentists. The advantages of one-piece immediate loading are to reduce the number of interventions. These parameters can be better controlled with a one-piece implant. METHODS: We considered 21 patients with one-piece implants inserted in mandible for this retrospective study. Inclusion criteria were: good oral hygiene, absence of lesions of the oral mucosa, no smoking or smoking less than 20 cigarettes a day, drinking less than two glasses of wine a day, good general health and no pregnancy. RESULTS: We enrolled 21 (12 women and 9 men) patients in this retrospective study. The mean follow-up was 1 year. A total of 84 one-piece implants were inserted in mandible to replace 42 lower first and 42 second incisors. The diameter of the implants was 3.0mm in all fixtures. The length of the implants was equal to or longer than 12mm in 44 and 40 fixtures respectively. Of these, 48 were inserted in women and 36 in men (age range 33 to 67; mean age 58.3 years). CONCLUSIONS: There is no difference between the survival rates of one-piece immediate loading implants and two-piece implants and delayed loading. In conclusion, a one-piece immediate loading implant is a reliable device for mandible rehabilitation