Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis

David H. Kim, James D. Beckett, Varun Nagpal, Manuel A. Seman-Senderos, Russell A. Gould, Tyler J. Creamer, Elena MacFarlane, Yichun Chen, Djahida Bedja, Jonathan T. Butcher, Wayne A Mitzner, Rosanne Rouf, Shoji Hata, Daniel Warren, Harry C Dietz

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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 Capn9 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.

Original languageEnglish (US)
Article numbereaau2814
JournalScience translational medicine
Volume11
Issue number501
DOIs
StatePublished - Jul 17 2019

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kim, D. H., Beckett, J. D., Nagpal, V., Seman-Senderos, M. A., Gould, R. A., Creamer, T. J., MacFarlane, E., Chen, Y., Bedja, D., Butcher, J. T., Mitzner, W. A., Rouf, R., Hata, S., Warren, D., & Dietz, H. C. (2019). Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal transition and fibrosis. Science translational medicine, 11(501), [eaau2814]. https://doi.org/10.1126/scitranslmed.aau2814