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Suppression of OGN in lung myofibroblasts attenuates pulmonary fibrosis by inhibiting integrin αv-mediated TGF-β/Smad pathway activation.
- Source :
-
Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2024 Sep; Vol. 132, pp. 87-97. Date of Electronic Publication: 2024 Jul 15. - Publication Year :
- 2024
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Abstract
- Background: Idiopathic pulmonary fibrosis (IPF) represents a severe and progressive manifestation of idiopathic interstitial pneumonia marked by an uncertain etiology along with an unfavorable prognosis. Osteoglycin (OGN), belonging to the small leucine-rich proteoglycans family, assumes pivotal functions in both tissue formation and damage response. However, the roles and potential mechanisms of OGN in the context of lung fibrosis remain unexplored.<br />Methods: The assessment of OGN expression levels in fibrotic lungs was conducted across various experimental lung fibrosis mouse models. To elucidate the effects of OGN on the differentiation of lung myofibroblasts, both OGN knockdown and OGN overexpression were employed in vitro. The expression of integrin αv, along with its colocalization with lysosomes and latency-associated peptide (LAP), was monitored in OGN-knockdown lung myofibroblasts. Furthermore, the role of OGN in lung fibrosis was investigated through OGN knockdown utilizing adeno-related virus serotype 6 (AAV6)-mediated delivery.<br />Results: OGN exhibited upregulation in both lungs and myofibroblasts across diverse lung fibrosis mouse models. And laboratory experiments in vitro demonstrated that OGN knockdown inhibited the TGF-β/Smad signaling pathway in lung myofibroblasts. Conversely, OGN overexpression promoted TGF-β/Smad pathway in these cells. Mechanistic insights revealed that OGN knockdown facilitated lysosome-mediated degradation of integrin αv while inhibiting its binding to latency-associated peptide (LAP). Remarkably, AAV6-targeted OGN knockdown ameliorated the extent of lung fibrosis in experimental mouse models.<br />Conclusion: Our results indicate that inhibiting OGN signaling could serve as a promising therapeutic way for lung fibrosis.<br />Competing Interests: Declaration of competing interest No conflicts of interest.<br /> (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Smad Proteins metabolism
Smad Proteins genetics
Humans
Gene Knockdown Techniques
Male
Pulmonary Fibrosis metabolism
Pulmonary Fibrosis genetics
Pulmonary Fibrosis pathology
Myofibroblasts metabolism
Myofibroblasts pathology
Signal Transduction
Integrin alphaV metabolism
Integrin alphaV genetics
Transforming Growth Factor beta metabolism
Transforming Growth Factor beta genetics
Disease Models, Animal
Idiopathic Pulmonary Fibrosis metabolism
Idiopathic Pulmonary Fibrosis pathology
Idiopathic Pulmonary Fibrosis genetics
Lung metabolism
Lung pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1569-1802
- Volume :
- 132
- Database :
- MEDLINE
- Journal :
- Matrix biology : journal of the International Society for Matrix Biology
- Publication Type :
- Academic Journal
- Accession number :
- 39019241
- Full Text :
- https://doi.org/10.1016/j.matbio.2024.07.001