Chondroprotective effects of glucosamine involving the p38 MAPK and Akt signaling pathways

Abstract

The purpose of the present study was to elucidate the possible signal transduction pathway involved in the underlying mechanism of glucosamine (GLN)'s influence on the gene expression of matrix metalloproteinases (MMPs) in chondrocytes stimulated with IL-1beta. Using chondrosarcoma cells stimulated with IL-1beta, the effects of GLN on the mRNA and protein levels of MMP-3, the activation of JNK, ERK, p38, NF-kappaB, and AP-1, the nuclear translocation of NF-kappaB/Rel family members, and PI3-kinase/Akt activation were studied. GLN inhibited the expression and the synthesis of MMP-3 induced by IL-1beta, and that inhibition was mediated at the level of transcription involving both the NF-kappaB and AP-1 transcription factors. Translocation of NF-kappaB was reduced by GLN as a result of the inhibition of IkappaB degradation. A slightly synergistic effect on the activation of AP-1 induced by IL-1beta was shown in the presence of GLN. Among MAPK pathways involved in the transcriptional regulation of AP-1, phosphorylation of JNK and ERK was found to increase with the presence of GLN under IL-1beta treatment, while that for p38 decreased. It was also found that GLN alone, but also synergistically with IL-1beta, was able to activate the Akt pathway. The requirements of NF-kappaB translocation and p38 activity are indispensably involved in the induction of MMP-3 expression in chondrosarcoma cells stimulated by IL-1beta. Inhibition of the p38 pathway in the presence of GLN substantially explains the chondroprotective effect of GLN on chondrocytes that regulate COX-2 expression, PGE(2) synthesis, and NO expression and synthesis. The chondroprotective effect of GLN through the decrease in MMP-3 production and stimulation of proteoglycan synthesis may follow another potential signaling pathway of Akt.

The Antagonistic Actions of Endogenous Interleukin-1β and 15-Deoxy-Δ12,14-prostaglandin J2 Regulate the Temporal Synthesis of Matrix Metalloproteinase-9 in Sheared Chondrocytes

“…Prior studies have identified the three major MAPKs (ERK1/2, JNK, and p38) (36,37) and PI3K (37) in transmitting IL-1␤-dependent signaling. In light of these findings (36,37), we evaluated the potential contributions of these signaling pathways to shear-induced MMP-9 synthesis.…”

“…In light of these findings (36,37), we evaluated the potential contributions of these signaling pathways to shear-induced MMP-9 synthesis. Shear stress rapidly up-regulates the activities of PI3K/Akt, ERK1/2, and JNK/ c-Jun (but not p38) pathways in human T/C-28a2 chondrocytes via an IL-1␤-dependent mechanism.…”

Scientific Opinion on the substantiation of a health claim related to glucosamine and maintenance of normal joint cartilage pursuant to Article 13(5) of Regulation (EC) No 1924/2006

“…A number of in vitro studies on the effect of glucosamine on cartilage formation/degradation were provided (Byron et al, 2008;Chan et al, 2005;Derfoul et al, 2007;Dodge and Jimenez, 2003;Largo et al, 2003;Lin et al, 2008;Lippiello, 2007;Lu et al, 2008;Sandy et al, 1999;Shikhman et al, 2001;Toegel et al, 2008;Uitterlinden et al, 2008;Varghese et al, 2007;Wei and Haut, 2009). The applicant was invited to provide a rationale on why any effects of glucosamine in vitro could predict effects in vivo in humans, taking into consideration the experimental conditions for these studies, e.g.…”

“…Regarding other proposed mechanisms, the evidence provided included references on in vitro effects of glucosamine on cartilage tissue explants and chondrocytes in culture, including effects of glucosamine on pro-inflammatory cytokines (Chan et al, 2005;Derfoul et al, 2007;Largo et al, 2003;Lin et al, 2008;Lu et al, 2008;Sandy et al, 1999;Shikhman et al, 2001;Toegel et al, 2008), and degradative enzymes (Derfoul et al, 2007;Dodge and Jimenez, 2003;Lin et al, 2008;Lu et al, 2008;Varghese et al, 2007). The Panel notes that the concentrations of glucosamine used in almost all of these studies considerably exceeded those that are achieved in blood and synovial fluid in humans with a daily intake of 1500 mg glucosamine.…”

The Glucosamine Controversy; A Pharmacokinetic Issue

“…Although results of such studies are often difficult to extrapolate to beneficial effects in humans, it appears that, indeed, GlcN does positively influence the biology of damaged issues. These studies ascribe anti-inflammatory properties to GlcN through inhibition of various pro-inflammatory mediators such as nitric oxide, cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMP) but mainly in the context of OA (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In addition to these mainly site specific studied, Hua et al (28), have reported the inhibitory effect of GlcN on the emergence of adjuvant arthritis (AA) in the rat (29).…”