title: Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype.
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.
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Midgley
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and.
authors.forename: Lucy
authors.initials: L
authors.lastname: Duggal
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and.
authors.forename: Robert
authors.initials: R
authors.lastname: Jenkins
authors.affiliation: the Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hascall
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and.
authors.forename: Robert
authors.initials: R
authors.lastname: Steadman
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and.
authors.forename: Aled O
authors.initials: AO
authors.lastname: Phillips
authors.affiliation: From the Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales, United Kingdom and merans@cf.ac.uk.
authors.forename: Soma
authors.initials: S
authors.lastname: Meran
mesh_terms: D001692:Biological Transport; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000235:genetics; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D027682:Cation Transport Proteins; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase
keywords: Bone Morphogenetic Protein (BMP); CD44; Hyaluronan; Hyaluronidase; Myofibroblast