title: HSPG modulation of BMP signaling in fibrodysplasia ossificans progressiva cells.
abstract: Cell surface heparan sulfate proteoglycans (HSPGs) play important roles in morphogen gradient formation and cell signaling. Bone morphogenetic protein (BMP) signaling is dysregulated in fibrodysplasia ossificans progressiva (FOP), a disabling disorder of progressive heterotopic bone formation. Here, we investigated the role of HSPG glycosaminoglycan (GAG) side chains on BMP signaling and found increased total and HSPG-specific GAG chain levels and dysregulation in HSPG modulation of BMP signaling in FOP lymphoblastoid cells (LCLs). Specifically, HSPG profiling demonstrated abundant mRNA and protein levels of glypican 1 and syndecan 4 on control and FOP LCLs, with elevated core protein levels on FOP cells. Targeted downregulation of glypican 1 core protein synthesis by siRNA enhanced BMP signaling in control and FOP cells, while reduction of syndecan 4-core protein synthesis decreased BMP signaling in control, but not FOP cells. These results suggest that FOP cells are resistant to the stimulatory effects of cell surface HSPG GAG chains, but are susceptible to the inhibitory effects, as shown by downregulation of glypican 1. These data support that HSPG modulation of BMP signaling is altered in cells from patients with FOP and that altered HSPG-related BMP signaling may play a role in the pathogenesis of the disease.
authors.affiliation: Department of Orthopaedic Surgery, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Connell
authors.forename: Paul C
authors.initials: PC
authors.lastname: Billings
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fiori
authors.forename: Gregory
authors.initials: G
authors.lastname: Deirmengian
authors.forename: Helmtrud I
authors.initials: HI
authors.lastname: Roach
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
mesh_terms: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D053673:Glypicans / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008751:Methylene Blue / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D009221:Myositis Ossificans / Q000378:metabolism*; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D053671:Syndecan-4 / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D051798:Inhibitor of Differentiation Protein 1; D008751:Methylene Blue; D011133:Polysaccharide-Lyases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053671:Syndecan-4; D000099176:Noggin Protein; C525809:BMP4 protein, human; C497453:ID1 protein, human; C435946:dimethylmethylene blue; C021349:heparitinsulfate lyase