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TISSUE-SPECIFIC STEM CELLS

Disruption of Heparan and Chondroitin Sulfate Signaling Enhances Mesenchymal Stem Cell-Derived Osteogenic Differentiation via Bone Morphogenetic Protein Signaling Pathways

^aInstitute of Molecular and Cell Biology, Singapore;
^bDepartment of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Key Words. Heparinase • Chondroitinase • Mesenchymal stem cell • Wnts • Osteoblast

Correspondence: Victor Nurcombe, Ph.D., Stem Cells and Tissue Repair Group, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673. Telephone: +65 6586 9714; Fax: +65 6779 1117; e-mail: vnurcombe{at}imcb.a-star.edu.sg

Received January 26, 2007; accepted for publication July 31, 2007.
First published online in STEM CELLS EXPRESS   August 16, 2007.



Cell surface heparan sulfate (HS) and chondroitin sulfate (CS) proteoglycans have been implicated in a multitude of biological processes, including embryonic implantation, tissue morphogenesis, wound repair, and neovascularization through their ability to regulate growth factor activity and morphogenic gradients. However, the direct role of the glycosaminoglycan (GAG) sugar-side chains in the control of human mesenchymal stem cell (hMSC) differentiation into the osteoblast lineage is poorly understood. Here, we show that the abundant cell surface GAGs, HS and CS, are secreted in proteoglycan complexes that directly regulate the bone morphogenetic protein (BMP)-mediated differentiation of hMSCs into osteoblasts. Enzymatic depletion of the HS and CS chains by heparinase and chondroitinase treatment decreased HS and CS expression but did not alter the expression of the HS core proteins perlecan and syndecan. When digested separately, depletion of HS and CS chains did not effect hMSC proliferation but rather increased BMP bioactivity through SMAD1/5/8 intracellular signaling at the same time as increasing canonical Wnt signaling through LEF1 activation. Long-term culturing of cells in HS- and CS-degrading enzymes also increased bone nodule formation, calcium accumulation, and the expression of such osteoblast markers as alkaline phosphatase, RUNX2, and osteocalcin. Thus, the enzymatic disruption of HS and CS chains on cell surface proteoglycans alters BMP and Wnt activity so as to enhance the lineage commitment and osteogenic differentiation of hMSCs.

Disclosure of potential conflicts of interest is found at the end of this article.