[Research Articles] Calpain 9 as a therapeutic target in TGF{beta}-induced mesenchymal transition and fibrosis

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, wit...

Source: Science Translational Medicine - July 16, 2019 Category: Biomedical Science Authors: Kim, D. H., Beckett, J. D., Nagpal, V., Seman-Senderos, M. A., Gould, R. A., Creamer, T. J., MacFarlane, E. G., Chen, Y., Bedja, D., Butcher, J. T., Mitzner, W., Rouf, R., Hata, S., Warren, D. S., Dietz, H. C. Tags: Research Articles Source Type: research