CoChat
Sign Up
Cited by 93Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisProteoglycans and glycosaminoglycans researchTelomeres, Telomerase, and Senescence

Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis

Open access
Li, Yuejuan, Liang, Jiurong, Yang, Ting, Monterrosa Mena, Jessica, Huan, Caijuan, Xie, Ting, Kurkciyan, Adrianne, Liu, Ningshan +2 more·2016·Matrix Biology
DOI 10.1016/j.matbio.2016.03.004PMC PMC5383204
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.matbio.2016.03.004

Cites

9 of 9 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Similar antifibrotic effects of senescent cells have been observed in the kidneys, liver and lungs in mouse models.

    “similar antifibrotic effects of senescent cells have been observed in the kidneys, liver and lungs in mouse models 10-12”

    From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [12]

    The Results (§2.7) describe senescent lung fibroblasts in bleomycin-treated mice, and the Introduction reports that targeted HAS2 deletion promotes senescence and resolution of pulmonary fibrosis. The Introduction and Discussion also report an antifibrotic role for senescence in liver fibrosis models. Our copy does not address antifibrotic effects of senescent cells in the kidneys. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Overexpression of an enzyme responsible for production of hyaluronan exacerbates bleomycin-induced injury, whereas its depletion appears to activate senescence.

    “In contrast, overexpression of an enzyme responsible for production of the extracellular matrix component hyaluronan exacerbates bleomycin-induced injury18, whereas its depletion appears to activate senescence, challenging a negative role for senescence in bleomycin-induced lung fibrosis19.”

    From Cellular senescence mediates fibrotic pulmonary disease (2017) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 54

  1. [2]ATS/ERS. American Thoracic Society Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS) Am J Respir Crit Care Med 161 2000 646 664 10673212
  2. [3]Moodley YP Caterina P Scaffidi AK Misso NL Papadimitriou JM McAnulty RJ Laurent GJ Thompson PJ Knight DA Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis J Pathol 202 2004 486 495 15095276
  3. [4]Henke C Bitterman P Roongta U Ingbar D Polunovsky V Induction of fibroblast apoptosis by anti-CD44 antibody: implications for the treatment of fibroproliferative lung disease Am J Pathol 149 1996 1639 1650 8909253 PMC1865279
  4. [5]Hadden HL Henke CA Induction of lung fibroblast apoptosis by soluble fibronectin peptides Am J Respir Crit Care Med 162 2000 1553 1560 11029376
  5. [6]Horowitz JC Rogers DS Simon RH Sisson TH Thannickal VJ Plasminogen activation induced pericellular fibronectin proteolysis promotes fibroblast apoptosis Am J Respir Cell Mol Biol 38 2008 78 87 17656680 PMC2176129
  6. [7]Campisi J d’Adda di Fagagna F Cellular senescence: when bad things happen to good cells Nat Rev Mol Cell Biol 8 2007 729 740 17667954
  7. [11]Tchkonia T Zhu Y van Deursen J Campisi J Kirkland JL Cellular senescence and the senescent secretory phenotype: therapeutic opportunities J Clin Invest 123 2013 966 972 23454759 PMC3582125
  8. [13]Araya J Kojima J Takasaka N Ito S Fujii S Hara H Yanagisawa H Kobayashi K Tsurushige C Kawaishi M Kamiya N Hirano J Odaka M Morikawa T Nishimura SL Kawabata Y Hano H Nakayama K Kuwano K Insufficient autophagy in idiopathic pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol 304 2013 L56 69 23087019
  9. [14]Aoshiba K Tsuji T Nagai A Bleomycin induces cellular senescence in alveolar epithelial cells Eur Respir J 22 2003 436 443 14516132
  10. [15]Jiang D Liang J Noble PW Regulation of non-infectious lung injury, inflammation, and repair by the extracellular matrix glycosaminoglycan hyaluronan Anat Rec (Hoboken) 293 2010 982 985 20186964 PMC2877145
  11. [16]Jiang D Liang J Noble P Hyaluronan as an Immune Regulator in Human Diseases Physiol Rev 91 2011 221 264 21248167 PMC3051404
  12. [17]Camenisch TD Spicer AP Brehm-Gibson T Biesterfeldt J Augustine ML Calabro A Jr Kubalak S Klewer SE McDonald JA Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme J Clin Invest 106 2000 349 360 10930438 PMC314332
  13. [18]Li Y Jiang D Liang J Meltzer EB Gray A Miura R Wogensen L Yamaguchi Y Noble PW Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44 J Exp Med 208 2011 1459 1471 21708929 PMC3135364
  14. [19]Lauer ME Dweik RA Garantziotis S Aronica MA The Rise and Fall of Hyaluronan in Respiratory Diseases Int J Cell Biol 2015 2015 712507 26448757 PMC4581576
  15. [20]Bjermer L Lundgren R Hallgren R Hyaluronan and type III procollagen peptide concentrations in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis Thorax 44 1989 126 131 2928996 PMC461712
  16. [21]Evanko SP Potter-Perigo S Petty LJ Workman GA Wight TN Hyaluronan Controls the Deposition of Fibronectin and Collagen and Modulates TGF-beta1 Induction of Lung Myofibroblasts Matrix Biol 42 2015 74 92 25549589 PMC4524654
  17. [22]Udabage L Brownlee GR Waltham M Blick T Walker EC Heldin P Nilsson SK Thompson EW Brown TJ Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer Cancer Res 65 2005 6139 6150 16024615
  18. [23]Reed MJ Damodarasamy M Chan CK Johnson MN Wight TN Vernon RB Cleavage of hyaluronan is impaired in aged dermal wounds Matrix Biol 32 2013 45 51 23022999 PMC3570623
  19. [24]Dimri GP Lee X Basile G Acosta M Scott G Roskelley C Medrano EE Linskens M Rubelj I Pereira-Smith O A biomarker that identifies senescent human cells in culture and in aging skin in vivo Proc Natl Acad Sci U S A 92 1995 9363 9367 7568133 PMC40985
  20. [25]Montagnoli A Fiore F Eytan E Carrano AC Draetta GF Hershko A Pagano M Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation Genes & development 13 1999 1181 1189 10323868 PMC316946
  21. [26]Polyak K Lee MH Erdjument-Bromage H Koff A Roberts JM Tempst P Massague J Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals Cell 78 1994 59 66 8033212
  22. [28]Noble PW Idiopathic pulmonary fibrosis: natural history and prognosis Clin Chest Med 27 2006 S11 16 16545628
  23. [30]Wynes MW Edelman BL Kostyk AG Edwards MG Coldren C Groshong SD Cosgrove GP Redente EF Bamberg A Brown KK Reisdorph N Keith RC Frankel SK Riches DW Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosis J Immunol 187 2011 527 537 21632719
  24. [31]Huang SK White ES Wettlaufer SH Grifka H Hogaboam CM Thannickal VJ Horowitz JC Peters-Golden M Prostaglandin E(2) induces fibroblast apoptosis by modulating multiple survival pathways FASEB J 23 2009 4317 4326 19671668 PMC2812040
  25. [32]Frankel SK Cosgrove GP Cha SI Cool CD Wynes MW Edelman BL Brown KK Riches DW TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis Am J Respir Cell Mol Biol 34 2006 293 304 16272460 PMC2644194
  26. [33]Jun JI Lau LF The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing Nature cell biology 12 2010 676 685 20526329 PMC2919364
  27. [34]Hecker L Logsdon NJ Kurundkar D Kurundkar A Bernard K Hock T Meldrum E Sanders YY Thannickal VJ Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance Sci Transl Med 6 2014 231ra247 PMC4545252 24718857
  28. [35]Simpson RM Meran S Thomas D Stephens P Bowen T Steadman R Phillips A Age-related changes in pericellular hyaluronan organization leads to impaired dermal fibroblast to myofibroblast differentiation Am J Pathol 175 2009 1915 1928 19808648 PMC2774056
  29. [36]Goldstein S Replicative senescence: the human fibroblast comes of age Science 249 1990 1129 1133 2204114
  30. [37]Suwan K Choocheep K Hatano S Kongtawelert P Kimata K Watanabe H Versican/PG-M Assembles Hyaluronan into Extracellular Matrix and Inhibits CD44-mediated Signaling toward Premature Senescence in Embryonic Fibroblasts J Biol Chem 284 2009 8596 8604 19164294 PMC2659218
  31. [38]Rock K Tigges J Sass S Schutze A Florea AM Fender AC Theis FJ Krutmann J Boege F Fritsche E Reifenberger G Fischer JW miR-23a-3p causes cellular senescence by targeting hyaluronan synthase 2: possible implication for skin aging The Journal of investigative dermatology 135 2015 369 377 25264594
  32. [39]Lompardia SL Papademetrio DL Mascaro M Alvarez EM Hajos SE Human leukemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy Glycobiology 23 2013 1463 1476 24013961
  33. [41]Denoyelle C Abou-Rjaily G Bezrookove V Verhaegen M Johnson TM Fullen DR Pointer JN Gruber SB Su LD Nikiforov MA Kaufman RJ Bastian BC Soengas MS Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway Nature cell biology 8 2006 1053 1063 16964246
  34. [42]Armanios MY Chen JJ Cogan JD Alder JK Ingersoll RG Markin C Lawson WE Xie M Vulto I Phillips JA 3rd Lansdorp PM Greider CW Loyd JE Telomerase mutations in families with idiopathic pulmonary fibrosis The New England journal of medicine 356 2007 1317 1326 17392301
  35. [43]Toussaint O Royer V Salmon M Remacle J Stress-induced premature senescence and tissue ageing Biochem Pharmacol 64 2002 1007 1009 12213599
  36. [44]Lin HK Chen Z Wang G Nardella C Lee SW Chan CH Yang WL Wang J Egia A Nakayama KI Cordon-Cardo C Teruya-Feldstein J Pandolfi PP Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence Nature 464 2010 374 379 20237562 PMC2928066
  37. [45]Campaner S Doni M Hydbring P Verrecchia A Bianchi L Sardella D Schleker T Perna D Tronnersjo S Murga M Fernandez-Capetillo O Barbacid M Larsson LG Amati B Cdk2 suppresses cellular senescence induced by the c-myc oncogene Nature cell biology 12 2010 54 59 51 14 20010815
  38. [46]Watanabe K Yamaguchi Y Molecular identification of a putative human hyaluronan synthase J Biol Chem 271 1996 22945 22948 8798477
  39. [47]Brinck J Heldin P Expression of recombinant hyaluronan synthase (HAS) isoforms in CHO cells reduces cell migration and cell surface CD44 Experimental cell research 252 1999 342 351 10527624
  40. [48]Kuroda Y Kasai K Nanashima N Nozaka H Nakano M Chiba M Yoneda M Nakamura T 4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate Biomed Res 34 2013 97 103 23594483
  41. [49]Simpson RM Wells A Thomas D Stephens P Steadman R Phillips A Aging fibroblasts resist phenotypic maturation because of impaired hyaluronan-dependent CD44/epidermal growth factor receptor signaling Am J Pathol 176 2010 1215 1228 20093489 PMC2832144
  42. [50]Lowe D Raj K Premature aging induced by radiation exhibits pro-atherosclerotic effects mediated by epigenetic activation of CD44 expression Aging Cell 13 2014 900 910 25059316 PMC4331742
  43. [51]Mun GI Boo YC Identification of CD44 as a senescence-induced cell adhesion gene responsible for the enhanced monocyte recruitment to senescent endothelial cells Am J Physiol Heart Circ Physiol 298 2010 H2102 2111 20382854
  44. [52]Bourguignon LY Matrix hyaluronan-activated CD44 signaling promotes keratinocyte activities and improves abnormal epidermal functions Am J Pathol 184 2014 1912 1919 24819962 PMC4076472
  45. [53]Debidda M Williams DA Zheng Y Rac1 GTPase regulates cell genomic stability and senescence J Biol Chem 281 2006 38519 38528 17032649
  46. [54]Costa ET Forti FL Matos TG Dermargos A Nakano F Salotti J Rocha KM Asprino PF Yoshihara CK Koga MM Armelin HA Fibroblast growth factor 2 restrains Ras-driven proliferation of malignant cells by triggering RhoA-mediated senescence Cancer Res 68 2008 6215 6223 18676845
  47. [55]Meran S Thomas D Stephens P Martin J Bowen T Phillips A Steadman R Involvement of hyaluronan in regulation of fibroblast phenotype J Biol Chem 282 2007 25687 25697 17611197
  48. [56]Li Y Rahmanian M Widstrom C Lepperdinger G Frost GI Heldin P Irradiation-induced expression of hyaluronan (HA) synthase 2 and hyaluronidase 2 genes in rat lung tissue accompanies active turnover of HA and induction of types I and III collagen gene expression Am J Respir Cell Mol Biol 23 2000 411 418 10970834
  49. [57]Li L Asteriou T Bernert B Heldin CH Heldin P Growth factor regulation of hyaluronan synthesis and degradation in human dermal fibroblasts: importance of hyaluronan for the mitogenic response of PDGF-BB Biochem J 404 2007 327 336 17324121 PMC1868797
  50. [58]Gauldie J Bonniaud P Sime P Ask K Kolb M TGF-beta, Smad3 and the process of progressive fibrosis Biochem Soc Trans 35 2007 661 664 17635115
  51. [59]Zhang HY Phan SH Inhibition of myofibroblast apoptosis by transforming growth factor beta(1) Am J Respir Cell Mol Biol 21 1999 658 665 10572062
  52. [60]Yamasaki M Kang HR Homer RJ Chapoval SP Cho SJ Lee BJ Elias JA Lee CG P21 regulates TGF-beta1-induced pulmonary responses via a TNF-alpha-signaling pathway Am J Respir Cell Mol Biol 38 2008 346 353 17932374 PMC2258454
  53. [61]Li Y Li L Brown TJ Heldin P Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells Int J Cancer 120 2007 2557 2567 17315194
  54. [62]Chai S Chai Q Danielsen CC Hjorth P Nyengaard JR Ledet T Yamaguchi Y Rasmussen LM Wogensen L Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis Circ Res 96 2005 583 591 15705963

Cited by

Sorted by citations

Authors
Li, Y., Liang, J., Yang, T., Monterrosa Mena, J., Huan, C., Xie, T., Kurkciyan, A., Liu, N., Jiang, D., & Noble, P. W.
Affiliations
  • Duke University (US)
  • Cedars-Sinai Medical Center (US)
Corresponding author
Noble, Paul W.
ORCID
Venue
Matrix Biology
Publisher
Elsevier BV
Published
2016-09
Volume
55
Pages
35-48
ISSN
0945-053X (ISSN-L)
DOI
10.1016/j.matbio.2016.03.004
PMC
PMC5383204
OpenAlex
W2301159868
Cited by
93
References
9
Citations by year
2026: 5 · 2025: 8 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 14 · 2017: 9 · 2016: 5
FWCI
11.33
Type
journal article
Language
en
Open access
Licence
Locations
  • Matrix Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (AI052201, HL060539, P01 HL108793, HL122068)
  • CIRM (RB5-07302)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
HAS2, pulmonary fibrosis, fibroblast senescence, replicative senescence, hyaluronic acid, bleomycin-induced lung fibrosis, mesenchymal cells, fibrosis resolution, therapeutic target
MeSH terms
Hyaluronan Synthases, Animals, Cells, Cultured, Fibroblasts, Humans, Mice, Transgenic, Pulmonary Fibrosis, Cellular Senescence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review