The effect of cathepsin K deficiency on airway development and TGF-β1 degradation

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-beta 1 degradation. Methods: We investigated the effects of cathepsin K-deficiency on alterations in airway integrity, extracellular matrix composition, and TGF-beta 1 expression and degradation. Lung homogenates of wild-type and cathepsin K-deficient mice were used to evaluate their contents of collagen, glycosaminoglycans, and TGF-beta 1. The accessibility of TGF-beta 1 to cathepsin K-mediated degradation was determined in vitro and lung fibroblast proliferations in wildtype 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 a-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-beta 1 expression by 25%. TGF-beta 1 proved an efficient substrate of cathepsin K and TGF-beta 1 protein content in lung was increased by a potent cathepsin inhibitor. Lung fibroblasts from Ctsk(-/-) mice after TGF-beta 1 treatment showed increased proliferation rates, increased levels of TGF-beta 1 by 30%, and increased ECM secretion. Conclusion: 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.