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

A prospective study on ultra-wide diameter dental implants for immediate molar replacement

Background: Although wide diameter implants are well documented, little is known about ultra-wide diameter implants (>6 mm). This study evaluates the clinical outcome of ultra-wide diameter implants, placed in molar extraction sockets. Materials and Methods: Ultra-wide diameter implants (7-9 mm) were placed immediately after molar extraction in a 1-stage protocol, without raising a flap or using any bone grafts. After 4 months, the implant was loaded with a single screw-retained crown. Bone loss was evaluated using peri-apical radiographs. Plaque and bleeding were recorded. Crown and papilla dimensions were measured and compared with the contra-lateral tooth. Results: Fifty-one patients (36 male and 15 female), mean ages 61 years old, were treated with 26 implants in the maxilla and 25 implants in the mandible. The majority had a thick (#19) or medium (#31) biotype. After a mean-follow-up period of 23 months, the mean bone level was located 1.16 mm apical of the implant-abutment junction (SD 0.42, range 0.00-2.45) while the actual bone remodeling associated with socket healing resulted in a mean coronal movement of the bone level of 0.15 mm. The mean insertion torque was 116 Ncm (SD 53, range 10-250). There were no differences in papilla height (P = .55), crown length (P = .32), zenith (P = .84), and bucco-palatal dimensions (P = .38). There was a significant difference in the mesio-distal dimension (P = .01). Mean probing depth was 2.59 mm at the implant and 2.23 mm at the contra-lateral tooth (P = .001). There was significantly more plaque at the tooth compared to the implant (P = .01), but there was no significant difference in terms of bleeding on probing (P = .08). Patient satisfaction was high with 72.5% of the patients experiencing no problems at all. Conclusions: Ultra-wide diameter implants have a predictable outcome, demonstrating very little bone loss. Papilla and crown dimensions were comparable to the contra-lateral natural tooth