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      Hyaluronan Regulates Bone Morphogenetic Protein-7-dependent Prevention and Reversal of Myofibroblast Phenotype*

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          Abstract

          Background: Bone morphogenetic protein-7 (BMP7) can prevent/reverse fibrosis, but mechanisms are unclear.

          Results: BMP7 prevents/reverses myofibroblast formation through cell-surface hyaluronan internalization into catalytic endosomes. Hyaluronidase-2 and variant CD44v7/8 mediate this process.

          Conclusion: Alterations in hyaluronan are critical in prevention/reversal of myofibroblast differentiation.

          Significance: A novel mechanism of BMP7 action is described and identifies CD44v7/8 and hyaluronidase-2 as potential targets in preventing fibrotic pathology.

          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.

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          Most cited references73

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          Transforming growth factor beta in tissue fibrosis.

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            BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.

            Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-beta1-induced de novo EMT in a mouse model of chronic renal injury. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-beta1 in the regulation of EMT in health and disease.
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              The myofibroblast in wound healing and fibrocontractive diseases.

              G Gabbiani (2003)
              The demonstration that fibroblastic cells acquire contractile features during the healing of an open wound, thus modulating into myofibroblasts, has open a new perspective in the understanding of mechanisms leading to wound closure and fibrocontractive diseases. Myofibroblasts synthesize extracellular matrix components such as collagen types I and III and during normal wound healing disappear by apoptosis when epithelialization occurs. The transition from fibroblasts to myofibroblasts is influenced by mechanical stress, TGF-beta and cellular fibronectin (ED-A splice variant). These factors also play important roles in the development of fibrocontractive changes, such as those observed in liver cirrhosis, renal fibrosis, and stroma reaction to epithelial tumours. Copyright 2003 John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                1 May 2015
                25 February 2015
                25 February 2015
                : 290
                : 18
                : 11218-11234
                Affiliations
                From the []Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and
                the [§ ]Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195
                Author notes
                [1 ] To whom correspondence should be addressed. Tel.: 44-2920748467; Fax: 44-2920748470; E-mail: merans@ 123456cf.ac.uk .
                Article
                M114.625939
                10.1074/jbc.M114.625939
                4416830
                25716319
                d8d75f72-993c-4731-8f4f-f7fbe68b987d
                © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version full access.

                Creative Commons Attribution Unported License applies to Author Choice Articles

                History
                : 13 November 2014
                : 16 February 2015
                Categories
                Glycobiology and Extracellular Matrices

                Biochemistry
                bone morphogenetic protein (bmp),cd44,hyaluronan,hyaluronidase,myofibroblast
                Biochemistry
                bone morphogenetic protein (bmp), cd44, hyaluronan, hyaluronidase, myofibroblast

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