title: Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis.
abstract: Dysregulated repair of lung injury often results in lung fibrosis characterized by unremitting deposition of matrix components including glycosaminoglycan hyaluronan (HA). HA is mainly produced by hyaluronan synthases (HAS) in mesenchymal cells. We previously demonstrated that over-expression of HAS2 in mesenchymal cells in mice regulates the invasiveness of fibroblasts and promotes severe lung fibrosis. The mechanisms that control the resolution of lung fibrosis are unknown. We propose that a critical step in resolving fibrosis is the induction of senescence in fibrotic fibroblasts and hyaluronan synthase 2 may regulate this process. We found that fibrotic fibroblasts developed the characteristics of replicative senescence in culture and that HAS2 expression was dramatically down-regulated. Furthermore, down-regulation of HAS2 initiated and regulated fibroblast senescence through a p27-CDK2-SKP2 pathway. Deletion of HAS2 in mouse mesenchymal cells increased the cellular senescence of fibroblasts in bleomycin-induced mouse lung fibrosis in vivo. These data suggest that HAS2 may be a critical regulator of the fate of pulmonary fibrosis and we propose a model where over-expression of HAS2 promotes an invasive phenotype resulting in severe fibrosis and down-regulation of HAS2 promotes resolution. Targeting HAS2 to induce fibroblast senescence could be an attractive approach to resolve tissue fibrosis.
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States; Pharmacology Department, JOINN Laboratories Inc., Suzhou 215421, China.
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Medicine, Duke University School of Medicine, Durham, NC 27710, United States; Department of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100013, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Monterrosa Mena
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States; Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, China.
authors.forename: Caijuan
authors.initials: C
authors.lastname: Huan
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Kurkciyan
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Ningshan
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States.
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States. Electronic address: paul.noble@cshs.org.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D000076002:Hyaluronan Synthases / Q000378:metabolism*; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology
chemical_list: C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases
keywords: Cell cycle; Fibrosis; Fibrosis resolution; Lung fibrosis; Matrix; Senescence