Chondroitin sulfate

From Shark cartilage

Chondroitin sulfate, one of five classes of glycosaminoglycans, has been widely used in the treatment of osteoarthritis. Chondroitin sulfate reduces inflammation mediators and the apoptotic process and is able to reduce protein production of inflammatory cytokines, iNOS and MMPs.

In Vitro:Chondroitin sulfate is a class of sulfated glycosaminoglycans that are linear polysaccharides consisting of repeating disaccharide units composed of uronic acid and N-acetylhexosamine. Several pathogens including parasites, bacteria, and viruses have been shown to utilize cell surface chondroitin sulfate chains to attach to and infect host cells[1]. Chondroitin sulfate occurs naturally in the extracellular matrix of connective tissues, e.g., bone, cartilage, skin, ligaments and tendons. Chondroitin sulfate has been shown to elicit a range of beneficial effects: anti-inflammatory effects, an increase in type II collagen and proteoglycans, a reduction in bone resorption and a better anabolic/catabolic balance in chondrocytes[2]. A large range of chondroitin sulfate concentrations has been used (e.g. 12.5 to 2000 mg/mL, but generally less than200 mg/mL) in in vitro studies. Chondroitin sulfate (200 mg/mL) decreases the chondrocyte susceptibility to single nucleotide polymorphism-induced apoptosis[3]. Chondroitin sulfate reduces inflammation mediators and the apoptotic process and is able to reduce protein production of inflammatory cytokines, iNOS, MMPs[4].

In Vivo:The high content of chondroitin sulfate in the aggrecan plays a major part in allowing cartilage to resist tensile stresses during various loading conditions by providing this tissue with resistance and elasticity. It has been shown that chondroitin sulphate interferes with the progression of structural changes in joint tissues and is used in the management of patients with osteoarthritis[3]. Chondroitin sulfate is mostly administered orally at doses ranging from 800 to 1200mg/day. Chondroitin sulfate is rapidly absorbed by the gastrointestinal tract. The absorbed chondroitin sulfate reaches the blood compartment as 10% chondroitin sulfate and 90% depolymerized low-molecular-weight derivatives[5].

References:
[1]. Mikami T, et al. Biosynthesis and function of chondroitin sulfate. Biochim Biophys Acta. 2013 Oct;1830(10):4719-33. [2]. Martel-Pelletier J, et al.Discrepancies in composition and biological effects of different formulations of chondroitin sulfate. Molecules. 2015 Mar 6;20(3):4277-89. [3]. Monfort J, et al. Biochemical basis of the effect of chondroitin sulphate on osteoarthritis articular tissues. Ann Rheum Dis. 2008 Jun;67(6):735-40. [4]. Campo GM, et al. Glycosaminoglycans modulate inflammation and apoptosis in LPS-treated chondrocytes. J Cell Biochem. 2009 Jan 1;106(1):83-92. [5]. Henrotin Y, et al. Chondroitin sulfate in the treatment of osteoarthritis: from in vitro studies to clinicalrecommendations. Ther Adv Musculoskelet Dis. 2010 Dec;2(6):335-48.

Anti-inflammatory activity of chondroitin sulfate.[Pubmed:18667340]

Osteoarthritis Cartilage. 2008;16 Suppl 3:S14-8.

Osteoarthritis is primarily characterized by areas of destruction of articular cartilage and by synovitis. Articular damage and synovitis are secondary to local increase of pro-inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha), enzymes with proteolytic activity (matrix metalloproteinases), and enzymes with pro-inflammatory activity (cyclooxygenase-2 and nitric oxide synthase-2). Enhanced expression of these proteins in chondrocytes and in synovial membrane appears associated to the activation and nuclear translocation of nuclear factor-kappaB (NF-kappaB). Chondroitin sulfate (CS) prevents joint space narrowing and reduces joint swelling and effusion. To produce these effects, CS elicits an anti-inflammatory effect at the chondral and synovial levels. CS and its disaccharides reduce NF-kappaB nuclear translocation, probably by diminishing extracellular signal-regulated kinase1/2, p38mitogen-activated protein kinase and c-Jun N-terminal kinase activation. This review discusses the evidence supporting that CS pleiotropic effects in chondrocytes and synoviocytes are primarily due to a common mechanism, e.g., the inhibition of NF-kappaB nuclear translocation.

Inhibitory effect of chondroitin sulfate oligosaccharides on bovine testicular hyaluronidase.[Pubmed:25659711]

Carbohydr Polym. 2015 May 5;121:362-71.

Hyaluronan and Chondroitin sulfates are prominent components of the extracellular matrices of animal tissues; however, their functions in relation to their oligosaccharide structures have not yet been fully elucidated. The oligosaccharides of hyaluronan and Chondroitin sulfate were prepared and used to investigate their effects on the hydrolysis and transglycosylation reactions of bovine testicular hyaluronidase when hyaluronan was used as a substrate. Hydrolysis and transglycosylation activities were assessed in independent reaction systems by analyzing the products by HPLC. The hydrolysis and transglycosylation reactions of bovine testicular hyaluronidase were dose-dependently inhibited by Chondroitin sulfate oligosaccharides, but not by hyaluronan or chondroitin oligosaccharides. A kinetic analysis of the hydrolysis reaction using hyaluronan octasaccharide revealed that the inhibition mode by Chondroitin sulfate oligosaccharides was competitive.

Chondroitin sulfate as a regulator of neuronal patterning in the retina.[Pubmed:1738848]

Science. 1992 Feb 7;255(5045):733-6.

Highly sulfated proteoglycans are correlated with axon boundaries in the developing central nervous system which suggests that these molecules affect neural pattern formation. In the developing mammalian retina, gradual regression of Chondroitin sulfate may help control the onset of ganglion cell differentiation and initial direction of their axons. Changes induced by the removal of Chondroitin sulfate from intact retinas in culture confirm the function of Chondroitin sulfate in retinal histogenesis.

TGF-ss Regulates Cathepsin Activation during Normal and Pathogenic Development.[Pubmed:29539424]

Cell Rep. 2018 Mar 13;22(11):2964-2977.

Cysteine cathepsins play roles during development and disease beyond their function in lysosomal protein turnover. Here, we leverage a fluorescent activity-based probe (ABP), BMV109, to track cysteine cathepsins in normal and diseased zebrafish embryos. Using this probe in a model of mucolipidosis II, we show that loss of carbohydrate-dependent lysosomal sorting alters the activity of several cathepsin proteases. The data support a pathogenic mechanism where TGF-ss signals enhance the proteolytic processing of pro-Ctsk by modulating the expression of chondroitin 4-sulfate (C4-S). In MLII, elevated C4-S corresponds with TGF-ss-mediated increases in chst11 expression. Inhibiting chst11 impairs the proteolytic activation of Ctsk and alleviates the MLII phenotypes. These findings uncover a regulatory loop between TGF-ss signaling and Ctsk activation that is altered in the context of lysosomal disease. This work highlights the power of ABPs to identify mechanisms underlying pathogenic development in living animals.

MicroRNAs in the axon locally mediate the effects of chondroitin sulfate proteoglycans and cGMP on axonal growth.[Pubmed:25788427]

Dev Neurobiol. 2015 Dec;75(12):1402-19.

Axonal miRNAs locally regulate axonal growth by modulating local protein composition. Whether localized miRNAs in the axon mediate the inhibitory effect of Chondroitin sulfate proteoglycans (CSPGs) on the axon remains unknown. We showed that in cultured cortical neurons, axonal application of CSPGs inhibited axonal growth and altered axonal miRNA profiles, whereas elevation of axonal cyclic guanosine monophosphate (cGMP) levels by axonal application of sildenafil reversed the effect of CSPGs on inhibition of axonal growth and on miRNA profiles. Specifically, CSPGs elevated and reduced axonal levels of miR-29c and integrin beta1 (ITGB1) proteins, respectively, while elevation of cGMP levels overcame these CSPG effects. Gain-of- and loss-of-function experiments demonstrated that miR-29c in the distal axon mediates axonal growth downstream of CSPGs and cGMP by regulating axonal protein levels of ITGB1, FAK, and RhoA. Together, our data demonstrate that axonal miRNAs play an important role in mediating the inhibitory action of CSPGs on axonal growth and that miR-29c at least partially mediates this process.

Chondroitin sulfate, one of five classes of glycosaminoglycans, has been widely used in the treatment of osteoarthritis. Chondroitin sulfate reduces inflammation mediators and the apoptotic process and is able to reduce protein production of inflammatory cytokines, iNOS and MMPs.

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