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The effect of cathepsin K deficiency on airway development and TGF-β1 degradation
Dongwei Zhang1, Nelson Leung, Ekkehard Weber
1The University of British Columbia, Department of Oral Biological and Medicinal Sciences, Vancouver, British Columbia, Canada.
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.
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.
Insights
Cathepsin K deficiency impairs airway integrity and lung development by affecting extracellular matrix and TGF-β1. These findings highlight the importance of considering lung effects when developing cathepsin K inhibitors.
Area of Science:
- Pulmonary Medicine
- Cell Biology
- Biochemistry
Background:
- Cathepsin K (Ctsk) is a protease targeted for osteoporosis treatment.
- Emerging evidence links Ctsk to non-skeletal functions, including lung fibrosis.
- The role of Ctsk in airway development and TGF-β1 regulation remains unclear.
Purpose of the Study:
- To investigate the role of Ctsk in airway development and integrity.
- To determine the effect of Ctsk on TGF-β1 expression and degradation in the lung.
Main Methods:
- Compared lung homogenates and airway histology from wild-type and Ctsk-deficient mice.
- Assessed extracellular matrix components (collagen, GAGs) and TGF-β1 levels.
- Evaluated TGF-β1 degradation by Ctsk in vitro and lung fibroblast proliferation.
Main Results:
- Ctsk deficiency led to increased airway epithelium thickness, reduced structural integrity, and elevated markers of fibrosis (α-actin, vimentin).
- Ctsk-deficient mice showed increased TGF-β1 expression and elevated hydroxyproline and GAGs content.
- TGF-β1 is a substrate for Ctsk; Ctsk inhibition increased lung TGF-β1 and fibroblast proliferation and ECM secretion.
Conclusions:
- Cathepsin K plays a role in regulating airway development and maintaining lung structural integrity.
- Therapeutic targeting of Cathepsin K requires careful consideration of potential adverse effects on lung tissue.
