Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity.
Bone morphogenetic proteins (BMPs) and their endogenous antagonists are important for brain and bone development and tumor initiation and progression. Heparan sulfate (HS) proteoglycans (HSPG) modulate the activities of BMPs and their antagonists. How glycosaminoglycans (GAGs) influence BMP activity in various malignancies and in inherited abnormalities of GAG metabolism, and the structural features of GAGs essential for modulation of BMP signaling, remain incompletely defined. We examined whether chemically modified soluble heparins, the endogenous HS in malignant cells and the HS accumulated in Hurler syndrome cells influence BMP-4 signaling and activity. We show that both exogenous (soluble) and endogenous GAGs modulate BMP-4 signaling and activity, and that this effect is dependent on specific sulfate residues of GAGs. Our studies suggest that endogenous sulfated GAGs promote the proliferation and impair differentiation of malignant human cells, providing the rationale for investigating whether pharmacological agents that inhibit GAG synthesis or function might reverse this effect. Our demonstration of impairment of BMP-4 signaling by GAGs in multipotent stem cells in human Hurler syndrome identifies a mechanism that might contribute to the progressive neurological and skeletal abnormalities in Hurler syndrome and related mucopolysaccharidoses.
Khan
Shaukat A
SA
Hematology and Oncology Section, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Nelson
Matthew S
MS
Pan
Chendong
C
Gaffney
Patrick M
PM
Gupta
Pankaj
P
D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D006023:Glycoproteins / Q000378:metabolism; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008059:Mucopolysaccharidosis I / Q000378:metabolism* / Q000473:pathology; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D013997:Time Factors
D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D006023:Glycoproteins; D006493:Heparin; D006497:Heparan Sulfate; D051798:Inhibitor of Differentiation Protein 1; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D051898:Smad1 Protein; C525809:BMP4 protein, human; C497453:ID1 protein, human; C497399:SMAD1 protein, human; C054234:chordin