Abstract
Osteoblastic cells produce a complex extracellular matrix (ECM) composed of a mixture of proteoglycans (PGs), collagens and non-collagenous proteins. The interaction of proteoglycans with matrix effector macromolecules via either their glycosaminoglycan (GAG) chains or their protein core is critical in regulating a variety of cellular events. Alterations in the structural composition of the GAG/PG component of the ECM may have important consequences on cell proliferation and / or differentiation. Human osteoblasts and two osteosarcoma cell lines, able to produce galactosaminoglycan (GalAGs) and heparan sulphate (HS)-containing proteoglycans, were treated with their main GAG chain types, and the effects on cell growth were examined. Chondroitin sulphate (CSA) and dermatan sulphate (DS) inhibited cell proliferation of all osteoblastic cell lines at high concentration (100 μg/ml). DS showed the stronger inhibitory effect, probably due to the presence of flexible IdoA residues that provide a greater variety in conformation to these macromolecules. Heparin strongly inhibited the proliferation rates of both normal osteoblasts and transformed osteoblastic cells at concentrations ≥1 μg/ml. The presence of large amounts of IdoA-derived trisulphated disaccharides, responsible for the overall negative charge of heparin, should be considered as a critical factor for the inhibition of cell proliferation. The obtained results suggest that matrix GAGs are factors which affect cell growth of both malignant and normal cells of the osteoblastic lineage in a concentration-dependent manner. This effect is closely related to the fine chemical structure of GAGs, i.e. the presence of L-iduronic acid and the degree of sulphation.
Footnotes
-
Abbreviations: GlcA, D-glucuronic acid; GlcN, D-glucosamine; Δdi-nonSHA, 2-acetamido-2-deoxy-3-O-(4-deoxy-α-L-threo-hex-4-enopyranosyluronic acid)-D-glucose; Δdi-nonSCS, 2-acetamido-2-deoxy-3-O-(4-deoxy-α-L-threo-hex-4-enopyranosyluronic acid)-D-galactose; Δdi-mono4S, Δdi-mono6S, Δdi-monoNS, monosulphated Δ-disaccharides at C-4, C-6 and the amino group of hexosamine, respectively; Δdi-mono2S, monosulphated Δ-disaccharides at C-2 of uronic acid and C-4 of hexosamine, respectively; Δdi-di(2,N)S and Δdi-di(6,N)S, disulphated Δ-disaccharides at C-2 of uronic acid and C-4 of hexosamine and at C-2 and C-6, respectively: Δdi-di(2,N)S and Δdi-di(6,N)S, disulphated Δ-disaccharides at C-2 of uronic acid and the amino group of hexosamine and at C-6 and the amino group, respectively; Δdi-tri(2,4,6)S, trisulphated Δ-disaccharides at C-2 of uronic acid and at C-4 and C-6 of hexosamine.
- Received December 2, 2004.
- Accepted April 14, 2005.
- Copyright© 2005 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved