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Altered heparan sulfate structure in Glce(-/-) mice leads to increased Hedgehog signaling in endochondral bones
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
Univ Duisburg Essen, Ctr Med Biotechnol, Essen, Germany..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2016 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 49, 82-92 p.Article in journal (Refereed) Published
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Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 49, 82-92 p.
Keyword [en]
Indian hedgehog, Ihh, Chondrocyte differentiation, Heparan sulfate, Epimerization, Glce, Endochondral ossification
National Category
Medical Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-283810DOI: 10.1016/j.matbio.2015.06.004ISI: 000371944000005PubMedID: 26116392OAI: oai:DiVA.org:uu-283810DiVA: diva2:919662
Funder
Swedish Research Council, K2012-67X-21128-01-4
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-11-30Bibliographically approved

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Dierker, TabeaLi, Jin-PingKjellen, Lena

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