title: The matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis.
abstract: Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, matrix stiffness is increasingly appreciated as a contributor to fibrosis rather than merely a manifestation of the disease. Here we show that the loss of Fibulin-5, an elastic fibre component, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis. These results suggest that Fibulin-5 may be a therapeutic target to short-circuit this profibrotic feedback loop.
authors.affiliation: IFOM-inSTEM Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis (inStem), NCBS GKVK Post, Bellary Road, Bangalore 560065, India.|Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors.forename: Manando
authors.initials: M
authors.lastname: Nakasaki
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors.forename: Yongsung
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: IFOM-inSTEM Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis (inStem), NCBS GKVK Post, Bellary Road, Bangalore 560065, India.
authors.forename: Sunny
authors.initials: S
authors.lastname: Kataria
authors.affiliation: IFOM-inSTEM Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis (inStem), NCBS GKVK Post, Bellary Road, Bangalore 560065, India.
authors.forename: Rupali
authors.initials: R
authors.lastname: Gund
authors.affiliation: IFOM-inSTEM Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis (inStem), NCBS GKVK Post, Bellary Road, Bangalore 560065, India.
authors.forename: Edries Y
authors.initials: EY
authors.lastname: Hajam
authors.affiliation: Center for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu 632004, India.
authors.forename: Rekha
authors.initials: R
authors.lastname: Samuel
authors.affiliation: Department of Dermatology, Venereology and Leprosy, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu 632004, India.
authors.forename: Renu
authors.initials: R
authors.lastname: George
authors.affiliation: Department of Rheumatology, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu 632004, India.
authors.forename: Debashish
authors.initials: D
authors.lastname: Danda
authors.affiliation: Department of Surgery, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu 632004, India.
authors.forename: Paul
authors.initials: P
authors.lastname: M J
authors.affiliation: Department of Pharmacology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0380, USA.
authors.forename: Zhouxin
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0380, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Briggs
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors.forename: Shyni
authors.initials: S
authors.lastname: Varghese
authors.affiliation: IFOM-inSTEM Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis (inStem), NCBS GKVK Post, Bellary Road, Bangalore 560065, India.|Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors.forename: Colin
authors.initials: C
authors.lastname: Jamora
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D018925:Chemokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D010641:Phenotype; D011994:Recombinant Proteins / Q000378:metabolism*; D012867:Skin / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: D018925:Chemokines; D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; D011994:Recombinant Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors