Bone resorption and remodeling in murine collagenase-induced osteoarthritis after administration of glucosamine

Nina Ivanovska,Petya Dimitrova

doi:10.1186/ar3283

Abstract

IntroductionGlucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage. Glucosamine has been clinically introduced for the treatment of osteoarthritis but the data about its protective role in disease are insufficient. The goal of this study was to investigate the effect of long term administration of glucosamine on bone resorption and remodeling.MethodsThe effect of glucosamine on bone resorption and remodeling was studied in a model of collagenase-induced osteoarthritis (CIOA). The levels of macrophage-inflammatory protein (MIP)-1α, protein regulated upon activation, normal T-cell expressed, and secreted (RANTES), soluble receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-α, and interleukin (IL)-6, 4 and 10 in synovial fluid were measured by enzyme-linked immunosorbent assay (ELISA). Cell populations in synovial extracts and the expression of RANKL, of receptors for TNF-α (TNF-αR) and interferon γ (IFN-γR) on clusters of differentiation (CD) three positive T cells were analyzed by flow cytometry. Transforming growth factor (TGF)-β3, bone morphogenetic protein (BMP)-2, phosphorylated protein mothers against decapentaplegic homolog 2 (pSMAD-2), RANKL and Dickkopf-1 protein (DKK-1) positive staining in CIOA joints were determined by immunohistochemistry.ResultsThe administration of glucosamine hydrochloride in CIOA mice inhibited loss of glycosaminoglycans (GAGs) and proteoglycans (PGs) in cartilage, bone erosion and osteophyte formation. It decreased the levels of soluble RANKL and IL-6 and induced IL-10 increase in the CIOA joint fluids. Glucosamine limited the number of CD11b positive Ly6G neutrophils and RANKL positive CD3 T cells in the joint extracts. It suppressed bone resorption via down-regulation of RANKL expression and affected bone remodeling in CIOA by decreasing BMP-2, TGF-β3 and pSMAD-2 expression and up-regulating DKK-1 joint levels.ConclusionsOur data suggest that glucosamine hydrochloride inhibits bone resorption through down-regulation of RANKL expression in the joints, via reduction of the number of RANKL positive CD3 T cells and the level of sRANKL in the joints extracts. These effects of glucosamine appear to be critical for the progression of CIOA and result in limited bone remodeling of the joints.

Highlights

Glucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage
Cytokine levels in the synovial extracts at Day 7 of collagenaseinduced osteoarthritis (CIOA) At Day 7 of CIOA, we found high levels of pro-inflammatory mediators macrophage-inflammatory protein (MIP)-1a, RANTES, soluble receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-a and IL-6 in the synovial extracts
Our data show that glucosamine acted on the arthritic process in joints through inhibition of neutrophils and, at least, partially of T cells, of CD3

Summary

Introduction

Glucosamine is an amino-monosaccharide and precursor of glycosaminoglycans, major components of joint cartilage. Glucosamine has been used for the treatment of osteoarthritis (OA) It is administered in different pharmacological forms, including sulfate, N-acetyl-glucosamine, or chlorohydrate salt [13]. Long-term oral treatment with this pharmacological form delayed the progression and improved the symptoms of knee osteoarthritis acting as a disease modifying agent [17]. It has been reported to exert improvement in OA [18], have a moderate effect [19] or show no difference with a placebo [20,21]. This variation in the results determines a need of more systemic investigations on the mechanisms of glucosamine action

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