title: The effect of cathepsin K deficiency on airway development and TGF-β1 degradation.
abstract: BACKGROUND
  Cathepsin K, a cysteine protease predominantly expressed in osteoclasts, is a major drug target for the treatment of osteoporosis. Recent findings, however, indicate that cathepsin K is also involved in non-skeletal metabolism. The development of fibrotic phenotypes in lung and skin is a concern for cathepsin K inhibitors presently evaluated in clinical trials. Cathepsin K is expressed in lung tissue and has been implicated in lung fibrosis. However, little is known about the role of cathepsin K in airway development and its effect on TGF-β1 degradation.
  
  
  METHODS
  We investigated the effects of cathepsin K-deficiency on alterations in airway integrity, extracellular matrix composition, and TGF-β1 expression and degradation. Lung homogenates of wild-type and cathepsin K-deficient mice were used to evaluate their contents of collagen, glycosaminoglycans, and TGF-β1. The accessibility of TGF-β1 to cathepsin K-mediated degradation was determined in vitro and lung fibroblast proliferations in wild-type and cathepsin K-deficient cells were evaluated.
  
  
  RESULTS
  Lung airway cathepsin K expression in wild-type mice remained constant between 1 and 6 months of age and the airway integrity was maintained. In contrast, after 2 months of age, all Ctsk-/- mice demonstrated increased airway epithelium thickness by 16-28%, a lower structural airway integrity (1-2 score units lower), elevated cytokeratin expression of 12%, increased α-actin and vimentin expression by 50% and 70%, increased area of smooth muscle cells by 15%, elevated hydroxyproline and GAGs content by 20% and 25%, and increased TGF-β1 expression by 25%. TGF-β1 proved an efficient substrate of cathepsin K and TGF-β1 protein content in lung was increased by a potent cathepsin inhibitor. Lung fibroblasts from Ctsk-/- mice after TGF-β1 treatment showed increased proliferation rates, increased levels of TGF-β1 by 30%, and increased ECM secretion.
  
  
  CONCLUSIONS
  This study suggests that airway development is partly regulated by cathepsin K and that its expression contributes to the maintenance of the airway structural integrity. The anticipated use of therapeutic cathepsin K inhibitors needs to take potential changes in human lungs into consideration.
authors.affiliation: The University of British Columbia, Department of Oral Biological and Medicinal Sciences, Vancouver, British Columbia, Canada.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Zhang
authors.forename: Nelson
authors.initials: N
authors.lastname: Leung
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D000367:Age Factors; D000375:Aging; D056151:Airway Remodeling; D000704:Analysis of Variance; D000818:Animals; D056657:Cathepsin K / Q000172:deficiency* / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D006025:Glycosaminoglycans / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000201:enzymology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing
chemical_list: D006025:Glycosaminoglycans; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen; D056657:Cathepsin K; C534132:Ctsk protein, mouse