Bone Resorption and Remodeling in Murine Collagenase-induced Osteoarthritis After Administration of Glucosamine

Nina Ivanovska; Petya Dimitrova

Disclosures

Arthritis Res Ther. 2011;13(2) 

In This Article

Abstract and Introduction

Abstract

Introduction: Glucosamine 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.
Methods: The 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.
Results: The 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.
Conclusions: Our 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.

Introduction

Glucosamine is one of the most abundant amino-monosaccharides immediately phosphorylated and included in a hexosamine biosynthesis pathway. The end-product of this pathway is UDP-N-acetylglucosamine, which is important for the synthesis of glycoaminoglycans and glycolipids. Exogenous glucosamine is bound with high affinity to glucose transporter GLUT-2[1] and can induce insulin resistance in adipocytes[2] and skeletal muscle cells.[3] In joint and cartilage, glucosamine can regulate the metabolism of glycosaminoglycans favoring catabolic processes. Glucosamine expresses a number of in vitro effects on chondrocytes, including stimulation of proteoglycan synthesis, inhibition of proteoglycan and collagen degradation, suppression of IL-1 induced activation and decrease of NF-κB activity.[4–8] Glucosamine has anti-inflammatory action suppressing inducible nitric oxide synthase (iNOS) expression,[9,10] neutrophil functions,[11] activation of T-lymphoblasts and dendritic cells.[12]

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] Oral application of glucosamine is more frequent, but experimental data about the effect of its intravenous injection have also been performed.[14] Glucosamine is absorbed from the gastrointestinal tract.[15] Depending on the pharmacological form used, its half-life in serum is from 28 h to 58 h.[14] Müller-Fassbender et al. have established that glucosamine sulfate is as effective as ibuprofen in patients with knee OA.[16] 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] In different trials, 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.

OA develops as a result of an imbalance between bone resorption and bone remodeling. Therefore, we have conducted this study to evaluate the effect of glucosamine on these processes mainly in the joint. Studies on its systemic effects were not in the focus of our experiments. Glucosamine was administered in an animal model of OA. We determined the levels of pro- and anti-inflammatory mediators and the phenotype of cells in the synovial extracts as well as the expression of resorption and remodeling markers in the joints.

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