Altered interaction and distribution of glycosaminoglycans and growth factors in mucopolysaccharidosis type I bone disease.
The mucopolysaccharidoses (MPSs) comprise a group of lysosomal storage disorders characterized by deficient degradation and subsequent accumulation of glycosaminoglycans (GAGs). Progressive bone and joint disease are a major cause of morbidity, and current therapeutic strategies have limited effect on these symptoms. By elucidating pathophysiological mechanisms underlying bone disease, new therapeutic targets may be identified. Longitudinal growth is regulated by interaction between GAGs and growth factors. Because GAGs accumulate in the MPSs, we hypothesized that altered interaction between growth factors and GAGs contribute to the pathogenesis of MPS bone disease. In this study, binding between GAGs from MPS I chondrocytes and fibroblast growth factor 2 (FGF2) was not significantly different from binding of FGF2 to GAGs from control chondrocytes. FGF2 signaling, however, was increased in MPS I chondrocytes after incubation with FGF2, as compared to control chondrocytes. Using bone cultures, we demonstrated decreased growth of WT mouse bones after incubation with FGF2, but no effect on MPS I bone growth. However, MPS I bones showed decreased growth in the presence of GAGs from MPS I chondrocytes. Finally, we demonstrate altered GAG distribution in MPS I chondrocytes, and altered GAG, FGF2 and Indian hedgehog distribution in growth plates from MPS I mice. In summary, our results suggest that altered interaction and distribution of growth factors and accumulated GAGs may contribute to the pathogenesis of MPS bone disease. In the future, targeting growth factor regulation or the interaction between in growth factors and GAGs might be a promising therapeutic strategy for MPS bone disease.
Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands; Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: s.d.kingma@amc.uva.nl.
Sandra D K
SDK
Kingma
Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands; Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: a.h.wagemans@amc.uva.nl.
Tom
T
Wagemans
Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: l.ijlst@amc.uva.nl.
Lodewijk
L
IJlst
Department of Oral Cell Biology ACTA, University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Gustav Mahlerlaan 3004, 1081, LA, Amsterdam, The Netherlands. Electronic address: a.bronckers@acta.nl.
Antonius L J J
ALJJ
Bronckers
Toin H. van Kuppevelt: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbus 9101, 6500, HB, Nijmegen, The Netherlands. Electronic address: Toin.vanKuppevelt@Radboudumc.nl.
Toin H
TH
van Kuppevelt
Department of Oral Cell Biology ACTA, University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Gustav Mahlerlaan 3004, 1081, LA, Amsterdam, The Netherlands. Electronic address: v.everts@acta.nl.
Vincent
V
Everts
Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: f.a.wijburg@amc.uva.nl.
Frits A
FA
Wijburg
Laboratory of Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands; Department of Pediatrics and Amsterdam Lysosome Centre "Sphinx", Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: n.vanvlies@amc.uva.nl.
Naomi
N
van Vlies
D000818:Animals; D001847:Bone Diseases / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D019902:Chondrocytes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism*; D006132:Growth Plate / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis
D006025:Glycosaminoglycans; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases
Bone disease; Fibroblast growth factor; Glycosaminoglycans; Growth factors; Indian hedgehog; Mucopolysaccharidosis