Heparan sulfate functions are altered in the osteoarthritic cartilage

Abstract

Background Heparan 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). Methods Glycosaminoglycans (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. Results In 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. Conclusion The 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.

Microbial dysbiosis and metabolic disorders promote rheumatoid arthritis across successive stages: a multi-omics cohort study

“…Additionally, total CAGs, CS, and heparan sulfate/heparin (HS/H) were reported to be higher in plasma of RA patients than in plasma of healthy subjects 27 . Moreover, the sulfation of HS was reported to be increased in cartilages of patients with OA 28 , and a decreased HS content or a reduced sulfation level was reported to protect against OA progression by regulating protease activity 25 . Thus, the significant depletion of HS degradation in microbial function would prevent HS from being degraded, promoting arthritis progression ( Fig.…”

“…24 We found that the significant depletion of DS degradation would inhibit the production of chondroitin 4-sulfate ( figure 3B ), which might hurt the mechanical properties of the articular cartilage. 24 Moreover, the significant depletion of HS degradation might be a potential cause of the higher plasma level of HS observed in RA and OA patients, 25,26 which could promote arthritis progression by regulating protease activity. 27 The most driving species of DS degradation and HS degradation were MGS Bacteroides uniformis and MGS Bacteroides plebeius , respectively.…”

“…Additionally, depleted B. plebeius drove the less degradation of HS. A high HS content would promote OA progression 25,28 . Second, increasing inflammation particularly in the second and the third of RA ( Fig.…”

Serpins in cartilage and osteoarthritis: what do we know?

“…Sulphation patterns of GAGs are critical to the binding of serpin exosites [ 81 ]. In cartilage, sulphation has been shown to be important for GAG binding of ADAMTS-5 and TIMP-3 [ 78 ], and the sulphation pattern of important cartilage GAGs changes in OA, which may impact on their function in the tissue [ 82 , 83 ].…”

Xanthohumol Attenuated Inflammation and ECM Degradation by Mediating HO-1/C/EBPβ Pathway in Osteoarthritis Chondrocytes

“…Osteoarthritis (OA), one of the age-related debilitating and degenerative diseases, is often clinically characterized by joint pain, limited movement, and transient morning stiffness ( Shamdani et al, 2020 ). Mechanistically, cartilage degradation, synovial inflammation, and subchondral bone remodeling are involved in the pathological development of OA ( Dai et al, 2017 ).…”