title: Altered heparan sulfate structure in Glce(-/-) mice leads to increased Hedgehog signaling in endochondral bones.
abstract: One of the key regulators of endochondral ossification is Indian hedgehog (Ihh), which acts as a long-range morphogen in the developing skeletal elements. Previous studies have shown that the distribution and signaling activity of Ihh is regulated by the concentration of the extracellular glycosaminoglycan heparan sulfate (HS). An essential step during biosynthesis of HS is the epimerization of D-glucuronic to L-iduronic acid by the enzyme glucuronyl C5-epimerase (Hsepi or Glce). Here we have investigated chondrocyte differentiation in Glce deficient mice and found increased regions of proliferating chondrocytes accompanied by a delayed onset of hypertrophic differentiation. In addition, we observed increased expression levels of the Ihh target genes Patched1 (Ptch1) and Parathyroid hormone related peptide (Pthrp; Parathyroid hormone like hormone (Pthlh)) indicating elevated Ihh signaling. We further show that Ihh binds with reduced affinity to HS isolated from Glce(-/-) mice. Together our results strongly indicate that not only the level, but also the structure of HS is critical in regulating the distribution and signaling activity of Ihh in chondrocytes.
authors.affiliation: Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany; Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Electronic address: tabea.dierker@imbim.uu.se.
authors.forename: Tabea
authors.initials: T
authors.lastname: Dierker
authors.affiliation: Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany. Electronic address: velina.bachvarova@uni-due.de.
authors.forename: Velina
authors.initials: V
authors.lastname: Bachvarova
authors.affiliation: Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany. Electronic address: yvonne.krause@uni-due.de.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Krause
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Electronic address: Jin-ping.Li@imbim.uu.se.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. Electronic address: lena.kjellen@imbim.uu.se.
authors.forename: Lena
authors.initials: L
authors.lastname: Kjellén
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry, Westfälische-Wilhelms University Münster, Münster, Germany. Electronic address: dgseidle@uni-muenster.de.
authors.forename: Daniela G
authors.initials: DG
authors.lastname: Seidler
authors.affiliation: Centre for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany. Electronic address: andrea.vortkamp@uni-due.de.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vortkamp
mesh_terms: D000818:Animals; D002238:Carbohydrate Epimerases / Q000172:deficiency*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism; D015576:Hyperostosis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019998:Racemases and Epimerases / Q000172:deficiency*; D015398:Signal Transduction
chemical_list: D002238:Carbohydrate Epimerases; D053823:Hedgehog Proteins; D006497:Heparan Sulfate; D019998:Racemases and Epimerases; C514061:ihh protein, mouse; C000612154:glucuronyl C5-epimerase, mouse
keywords: Chondrocyte differentiation; Endochondral ossification; Epimerization; Glce; Heparan sulfate; Ihh; Indian hedgehog