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Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype

Midgley, Adam Christopher, Druggal, Lucy, Jenkins, Robert, Hascall, Vincent, Steadman, Robert, Phillips, Aled Owain and Meran, Soma 2015. Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype. The Journal of Biological Chemistry 129 , pp. 11218-11234. 10.1074/jbc.M114.625939

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Abstract

Hyaluronan (HA) promotes transforming growth factor (TGF)-β1-driven myofibroblast phenotype. However, HA can also have disease-limiting activity. Bone morphogenetic protein-7 (BMP7) is an antifibrotic cytokine that antagonizes TGF-β1, and isolated studies have demonstrated that HA can both mediate and modulate BMP7 responses. In this study, we investigated whether BMP7 can modulate HA in a manner that leads to prevention/reversal of TGF-β1-driven myofibroblast differentiation in human lung fibroblasts. Results demonstrated that BMP7 prevented and reversed TGF-β1-driven myofibroblast differentiation through a novel mechanism. BMP7 promoted the dissolution and internalization of cell-surface HA into cytoplasmic endosomes. Endosomal HA co-localized with the HA-degrading enzymes, hyaluronidase-1 and hyaluronidase-2 (Hyal2). Moreover, BMP7 showed differential regulation of CD44 standard and variant isoform expression, when compared with TGF-β1. In particular, BMP7 increased membrane expression of CD44v7/8. Inhibiting CD44v7/8 as well as blocking Hyal2 and the Na+/H+ exchanger-1 at the cell-surface prevented BMP7-driven HA internalization and BMP7-mediated prevention/reversal of myofibroblast phenotype. In summary, a novel mechanism of TGF-β1 antagonism by BMP7 is shown and identifies alteration in HA as critical in mediating BMP7 responses. In addition, we identify Hyal2 and CD44v7/8 as new potential targets for manipulation in prevention and reversal of fibrotic pathology.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: Medical Research Council, Kidney Research UK
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 25 February 2015
Last Modified: 19 Jun 2019 20:03
URI: http://orca-mwe.cf.ac.uk/id/eprint/73194

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