Experimental pharmacology of glucosamine sulfate

Abstract

Several clinical studies demonstrated that glucosamine sulfate (GS) is effective in controlling osteoarthritis (OA), showing a structure-modifying action. However, little is known about the molecular mechanism(s) by which GS exerts such action and about the effects of GS at a tissue level on osteoarthritic cartilage and other joint structures. Here we provide mechanistic evidence suggesting that in vitro GS attenuates NF-κB activation at concentrations in the range of those observed after GS administration to volunteers and patients, thus strengthening previous findings. Furthermore, we describe the effects of GS at a tissue level on the progression of the disease in a relevant model of spontaneous OA, the STR/ort mouse. In this model, the administration of GS at human corresponding doses was associated with a significant decrease of OA scores. Histomorphometry showed that the lesion surface was also significantly decreased, while the number of viable chondrocytes within the matrix was significantly increased. GS improved the course of OA in the STR/Ort mouse, by delaying cartilage breakdown as assessed histologically and histomorphometrically.

Figure 1

Effect of GS on IL-1β-induced gene expression of IL-1β (a), COX-2 (b), IL-6 (c), and TNFα (d). One hour after the pretreatment with GS (0,1–100 μM), SW1353 are stimulated with IL-1β (2 ng/mL) as indicated. Representative pictures of 3 to 5 independent experiments are shown. Data are mean ± SD of three replicates.

Figure 2

Effect of GS on IL-1β-induced gene expression of MMP-3 (a) and ADAM-TS5 (b). One hour after the pretreatment with GS (0,1–100 μM), SW1353 are stimulated with IL-1β (2 ng/mL) as indicated. Representative pictures of 3 to 5 independent experiments are shown. Data are mean ± SD of three replicates.

Figure 3

Effect of GS on IL-1β-induced gene expression of NF-κB1/p50 (a), NF-κB2/p52 (b), RelB (c), and JunB (d). One hour after the pre-treatment with GS (0,001–100 μM), SW1353 are stimulated with IL-1β (10 ng/mL) for 2 h. Representative pictures of 3 to 5 independent experiments are shown. Data are mean ± SD of three replicates.

Figure 4

Representative histology images of articular cartilage from 8-month-old STR/ort mice that were treated with GS 200 mg/kg (b) or vehicle (a) for 3 months.

Figure 5

(a) Effect of subcutaneous administration of GS on OARSI score in STR/ort mice. Data are represented as median. (b) Effect of subcutaneous administration of GS on Lesion surface/total surface in STR/ort mice. Data are represented as mean ± SE. (c) Effect of subcutaneous administration of GS on n. of viable cells/total cartilage volume in STR/ort mice. Data are represented as mean ± SE. * = P < 0.05 versus vehicle (ANOVA). The vehicle group is always statistically different from the naïve 5-month-old group.