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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis
Science translational medicine, v 11(501), eaau2814
17 Jul 2019
PMCID: 7351287
PMID: 31316008
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Fibrosis is a common pathologic outcome of chronic disease resulting in the replacement of normal tissue parenchyma with a collagen-rich extracellular matrix produced by myofibroblasts. Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues and diseases, their contribution to fibrosis initiation, maintenance, and progression is thought to be pervasive. Here, we showed that the ability of transforming growth factor-β (TGFβ) to efficiently induce myofibroblast differentiation of cultured epithelial cells, endothelial cells, or quiescent fibroblasts is dependent on the induced expression and activity of dimeric calpains, a family of non-lysosomal cysteine proteases that regulate a variety of cellular events through posttranslational modification of diverse substrates. siRNA-based gene silencing demonstrated that TGFβ-induced mesenchymal transition of a murine breast epithelial cell line was dependent on induction of expression of calpain 9 (CAPN9), an isoform previously thought to be restricted to the gastrointestinal tract. Mice lacking functional CAPN9 owing to biallelic targeting of
were viable and fertile but showed overt protection from bleomycin-induced lung fibrosis, carbon tetrachloride-induced liver fibrosis, and angiotensin II-induced cardiac fibrosis and dysfunction. A predicted loss-of-function allele of CAPN9 is common in Southeast Asia, with the frequency of homozygosity matching the prediction of Hardy-Weinberg equilibrium. Together with the highly spatially restricted pattern of CAPN9 expression under physiologic circumstances and the heartiness of the murine knockout, these data provide a strong signature for tolerance of therapeutic strategies for fibrosis aimed at CAPN9 antagonism.
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Details
- Title
- Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis
- Creators
- David H Kim - Johns Hopkins MedicineJames D Beckett - Johns Hopkins MedicineVarun Nagpal - Johns Hopkins MedicineManuel A Seman-Senderos - Johns Hopkins MedicineRussell A Gould - Johns Hopkins MedicineTyler J Creamer - Johns Hopkins MedicineElena Gallo MacFarlane - Johns Hopkins MedicineYichun Chen - Johns Hopkins MedicineDjahida Bedja - Johns Hopkins MedicineJonathan T Butcher - Cornell UniversityWayne Mitzner - Johns Hopkins UniversityRosanne Rouf - Johns Hopkins MedicineShoji Hata - Tokyo Metropolitan Institute of Medical ScienceDaniel S Warren - Johns Hopkins MedicineHarry C Dietz - Howard Hughes Medical Institute
- Publication Details
- Science translational medicine, v 11(501), eaau2814
- Publisher
- American Association for the Advancement of Science (AAAS)
- Grant note
- S10 OD016374 / NIH HHS S10 RR024550 / NCRR NIH HHS Howard Hughes Medical Institute R01 HL128745 / NHLBI NIH HHS T32 GM007814 / NIGMS NIH HHS T32 GM007309 / NIGMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000475849000002
- Scopus ID
- 2-s2.0-85069896680
- Other Identifier
- 991021229908004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Medicine, Research & Experimental