Heparan sulfate functions are altered in the osteoarthritic cartilage

Abstract

BackgroundHeparan sulfate (HS) proteoglycans (PG) may be found at the chondrocyte surface and in the pericellular cartilage matrix, and are involved in cell-cell and cell-matrix interactions. An important function of HS chains is to regulate cell fate through specific interactions with heparin-binding proteins (HBP) modulated by their complex sulfation pattern. Osteoarthritis (OA) is a joint disorder characterized by the degradation of articular cartilaginous extracellular matrix. The aim of this study was to investigate HS structure and functions in osteoarthritic cartilages compared to normal cartilages (controls).MethodsGlycosaminoglycans (GAG) were extracted from human macroscopically normal cartilages (controls, n = 7) and (OA cartilages n = 11). HS were isolated and quantified using the DMMB quantification method. Their structure and functions were then compared using respectively a HPLC analysis and HBP binding tests and their phenotypic effects on murine chondrocytes were studied by RQ-PCR. Statistical analyzes were performed using a one-way ANOVA followed by a Dunnett’s test or a t test for pairwise comparisons.ResultsIn OA, HS were characterized by increased sulfation levels compared to controls. Moreover, the capacity of these HS to bind HBP involved in the OA pathophysiological process such as FGF2 and VEGF was reduced. Chondroitin sulfates and keratan sulfates regulated these binding properties. Finally, HS from OA cartilages induced the mRNA levels of catabolic markers such as MMP3, MMP13, and TS4 and inhibited the mRNA levels of anabolic markers such as COL2, ACAN, SOX9, and VEGF in murine articular chondrocytes.ConclusionThe sulfation of HS chains was increased in OA cartilages with changes in HBP binding properties and biological effects on chondrocyte phenotypes. Thus, modified HS present in altered cartilages could be a novel therapeutic target in OA.