heparitin-sulfate and Osteoarthritis

Osteoarthritis (OA) is a chronic disease that degrades the joints and is often associated with increasing age and obesity. The two most common sites of OA in adults are the knee and hip joints. Increased mechanical stress on the joint from obesity can cause the articular cartilage to degrade and release damage-associated molecular patterns (DAMPs). These DAMPs are involved in various molecular pathways that interact with nuclear factor-kappa B and result in the transcription of inflammatory cytokines and activation of matrix metalloproteinases that progressively destroy cartilage. This review focuses on the interactions and contribution to the pathogenesis and progression of OA through the DAMPs: high-mobility group box 1 (HMGB-1), the receptor for advanced glycation end-products (RAGE), the alarmin proteins S100A8 and S100A9, and heparan sulfate. HMGB-1 is released from damaged or necrotic cells and interacts with toll-like receptors (TLRs) and RAGE to induce inflammatory signals, as well as behave as an inflammatory cytokine to activate innate immune cells. RAGE interacts with HMGB-1, advanced glycation end-products, and innate immune cells to increase local inflammation. The alarmin proteins are released following cell damage and interact through TLRs to increase local inflammation and cartilage degradation. Heparan sulfate has been shown to facilitate the binding of HMGB-1 to RAGE and could play a role in the progression of OA. Targeting these DAMPs may be the potential therapeutic strategies for the treatment of OA.

Topics: Animals; Heparitin Sulfate; Humans; Osteoarthritis; Receptor for Advanced Glycation End Products; S100 Proteins

Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide.

Topics: Aged; Aggrecans; Cartilage, Articular; Heparitin Sulfate; Humans; Osteoarthritis; Sodium; Transforming Growth Factor beta

Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown.. Sdc4 immunostaining was performed on rheumatoid arthritis (RA) tissue sections. Interleukin (IL)-1 induced extracellular signal-regulated kinases (ERK) phosphorylation and matrix metalloproteinase-3 production was investigated. Il-1 binding to sdc4 was investigated using immunoprecipitation. IL-1 receptor (IL1R1) staining on wild-type, sdc4 and IL1R1 knockout fibroblasts was performed in fluorescence-activated cell sorting analyses. A blocking sdc4 antibody was used to investigate sdc4 dimerisation, IL1R1 expression and the histological paw destruction in the human tumour necrosis factor-alpha transgenic mouse.. We show that in fibroblasts, the loss of sdc4 or the antibody-mediated inhibition of sdc4 dimerisation reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. We demonstrate that IL-1 directly binds to sdc4 and in an IL-1R-independent manner leads to its dimerisation. IL-1-induced dimerisation of sdc4 regulates caveolin vesicle-mediated trafficking of the IL1R1, which in turn determines the responsiveness to IL-1. Administration of antibodies (Ab) against the dimerisation domain of sdc4, thus, strongly reduces the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA.. Collectively, our data suggest that Ab that specifically inhibit sdc4 dimerisation may support anti-IL-1 strategies in diseases such as inflammatory arthritis.

Topics: Animals; Antibodies, Blocking; Arthritis, Rheumatoid; Dimerization; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Knockout Techniques; Heparitin Sulfate; Hindlimb; Humans; Interleukin-1; Interleukin-1beta; MAP Kinase Signaling System; Matrix Metalloproteinase 3; Mice; Mice, Transgenic; NIH 3T3 Cells; Osteoarthritis; Phosphorylation; Protein Transport; Receptors, Interleukin-1 Type I; Signal Transduction; Syndecan-4; Synovial Membrane; Tumor Necrosis Factor-alpha

Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression.. To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1. All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1. A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression.

Topics: Aggrecans; Animals; Anterior Cruciate Ligament; Blotting, Western; Cartilage, Articular; Chondrocytes; Disease Models, Animal; Disease Progression; Heparitin Sulfate; Loss of Function Mutation; Matrix Metalloproteinase 2; Mice; Mice, Transgenic; N-Acetylglucosaminyltransferases; Osteoarthritis; Real-Time Polymerase Chain Reaction; Sulfotransferases

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).. 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.. 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.. 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.

Topics: Animals; Cartilage, Articular; Chondrocytes; Glycosaminoglycans; Heparitin Sulfate; Humans; Mice; Osteoarthritis

The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.

Topics: ADAM Proteins; ADAM12 Protein; Animals; Catalytic Domain; Cell Line; Cell Membrane; Cricetinae; Enzyme Activation; Glucuronidase; Glycosaminoglycans; Heparitin Sulfate; Humans; Membrane Proteins; Osteoarthritis; Protein Binding; Substrate Specificity

Glycosaminoglycans in normal and osteoarthrotic temporomandibular joint disks were studied by means of high-performance liquid chromatography methods. Normal disk tissue contains galactosaminoglycans (chondroitin sulfate and dermatan sulfate) as the main polysaccharides and with smaller amounts of hyaluronate and heparan sulfate. The galactosaminoglycans are mainly sulfated in 6-position, and some of the disaccharides contain iduronic acid. There was a slight general variation in glycosaminoglycan concentration with increasing age. In the severely arthrotic disks the content of glycosaminoglycans was considerably lower than in normal disk tissue. This decrease was far more extensive than that observed in relation to age in normal tissue. The 4/6-sulfate ratio of the galactosaminoglycans was increased, whereas the proportion of iduronic acid was markedly decreased.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cartilage, Articular; Chondroitin Sulfates; Chromatography, High Pressure Liquid; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Keratan Sulfate; Male; Middle Aged; Osteoarthritis; Temporomandibular Joint; Temporomandibular Joint Disorders