Dopamine D1 receptor stimulates cathepsin K-dependent degradation and resorption of collagen I in lung fibroblasts
Abstract
Matrix resorption is essential to the clearance of ECM after normal wound healing. A disruption in these processes constitutes a main component of fibrotic diseases, characterized by excess deposition and diminished clearance of fibrillar ECM proteins such as collagen type I. The mechanisms and stimuli regulating ECM resorption in the lung remain poorly understood. Recently, agonism of Dopamine Receptor D1 (DRD1), which is predominantly expressed on fibroblasts in the lung, has been shown to accelerate tissue repair and clearance of ECM following bleomycin injury in mice. Therefore, we investigated whether DRD1 receptor signaling promotes the degradation of collagen type I by lung fibroblasts. In cultured fibroblasts we found that DRD1 agonism enhances extracellular cleavage, internalization and lysosomal degradation of collagen I mediated by Cathepsin K, which results in reduced stiffness of cell-derived matrices measured by atomic force microscopy. In vivo agonism of DRD1 similarly enhanced fibrillar collagen degradation by fibroblasts, as assessed by tissue labelling with a collagen hybridizing peptide. Together these results implicate DRD1 agonism in fibroblast-mediated collagen clearance, suggesting an important role for this mechanism in fibrosis resolution.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2020
- Source ID
- 10.1242/jcs.248278
Entities
People
- Ana M. Diaz-espinosa
- Andrew J Haak
- Daniel J Tschumperlin
- Delphine Sicard
- Ignasi Jorba
- Patrick A. Link
Organizations
- American Lung Association
- Boehringer Ingelheim
- Mayo Clinic
- National Institutes of Health
- Pulmonary Fibrosis Foundation
- United States Department of Defense