title: Regulation of Hyaluronan (HA) Metabolism Mediated by HYBID (Hyaluronan-binding Protein Involved in HA Depolymerization, KIAA1199) and HA Synthases in Growth Factor-stimulated Fibroblasts.
abstract: Regulation of hyaluronan (HA) synthesis and degradation is essential to maintenance of extracellular matrix homeostasis. We recently reported that HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization), also called KIAA1199, plays a key role in HA depolymerization in skin and arthritic synovial fibroblasts. However, regulation of HA metabolism mediated by HYBID and HA synthases (HASs) under stimulation with growth factors remains obscure. Here we report that TGF-β1, basic FGF, EGF, and PDGF-BB commonly enhance total amount of HA in skin fibroblasts through up-regulation of HAS expression, but molecular size of newly produced HA is dependent on HYBID expression levels. Stimulation of HAS1/2 expression and suppression of HYBID expression by TGF-β1 were abrogated by blockade of the MAPK and/or Smad signaling and the PI3K-Akt signaling, respectively. In normal human skin, expression of the TGF-β1 receptors correlated positively with HAS2 expression and inversely with HYBID expression. On the other hand, TGF-β1 up-regulated HAS1/2 expression but exerted only a slight suppressive effect on HYBID expression in synovial fibroblasts from the patients with osteoarthritis or rheumatoid arthritis, resulting in the production of lower molecular weight HA compared with normal skin and synovial fibroblasts. These data demonstrate that although TGF-β1, basic FGF, EGF, and PDGF-BB enhance HA production in skin fibroblasts, TGF-β1 most efficiently contributes to production of high molecular weight HA by HAS up-regulation and HYBID down-regulation and suggests that inefficient down-regulation of HYBID by TGF-β1 in arthritic synovial fibroblasts may be linked to accumulation of depolymerized HA in synovial fluids in arthritis patients.
authors.affiliation: From the Biological Science Research and.
authors.forename: Aya
authors.initials: A
authors.lastname: Nagaoka
authors.affiliation: From the Biological Science Research and yoshida.hiroyuki2@kao.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: From the Biological Science Research and.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: From the Biological Science Research and.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: From the Biological Science Research and.
authors.forename: Keigo
authors.initials: K
authors.lastname: Kawabata
authors.affiliation: From the Biological Science Research and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Health Beauty Products Research, Kao Corporation, 3-28, 5-chome, Kotobuki-cho, Odawara-shi, Kanagawa, 250-0002 Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakai
authors.affiliation: From the Biological Science Research and.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016 Japan, and okada@z6.keio.jp.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Kanebo Cosmetics Inc., 1-14-10, Nihonbashi Kayabacho, Chuo-ku, Tokyo, 103-8210 Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Inoue
mesh_terms: D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D018125:Receptors, Transforming Growth Factor beta; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases; C491433:CEMIP protein, human; D006821:Hyaluronoglucosaminidase
keywords: KIAA1199/HYBID; arthritis; catabolism; cell signaling; fibroblast; growth factor; hyaluronan; hyaluronan synthase; skin; transforming growth factor beta (TGF-B)