Session Title: Cytokines, Mediators, and Gene Regulation
Session Type: Abstract Submissions (ACR)
Some proteolytic products of cartilage matrix may contribute to cartilage destruction through their catabolic activities. Recently, we have found that a 24-mer synthetic peptide of type II collagen named CB12-II stimulates type II collagen cleavage with induction of matrix metalloproteinase (MMP)-13 in cartilage explant culture. Although the intracellular signaling that leads to cartilage destruction is mediated by a cluster of catabolic pathways including nuclear factor-κB (NF-κB), the effect of CB12-II on NF-κB remains unclear.
Hyaluronan (HA) of high molecular weight is widely used in the treatment of osteoarthritis (OA) by intra-articular injection. An increasing body of evidence indicates that HA suppresses catabolic actions by proinflammatory cytokines like interleukin-1 and matrikines such as fibronectin fragments. However, little is known of HA effect on actions of CB12-II through interaction with HA receptor such as CD44.
This study was aimed to examine activation of NF-κB in association with MMP-13 production by CB12-II and its inhibition by HA in chondrocytes.
Cartilage explants harvested from OA knee joints or isolated chondrocytes in monolayer were incubated with CB12-II or its scramble peptide with or without pretreatment with 2700 kDa HA. In another set of experiments, following preincubation with anti-CD44 antibody or non-specific IgG, cartilage explants were incubated with or without HA, followed by coincubation with CB12-II or the scramble peptide.
Enzyme-linked immunosorbent assays for phosphorylated p65 NF-κB and MMP13 were performed using total cell lysates and culture supernatants, respectively.
When cartilage explants or chondrocytes in monolayer were incubated with CB12-II, the type II collagen peptide activated NF-κB in association with enhanced MMP-13 production. Inhibition studies with the specific inhibitor indicated the requirement of NF-κB for CB12-II-induced MMP-13 production. Pretreatment with HA resulted in significant suppression of CB12-II-stimulated MMP-13 production in cartilage as well as in chondrocyte monolayer cultures. HA suppressed NF-κB activation by CB12-II, leading to a decrease in MMP-13 production. Anti-CD44 antibody reversed HA effect on CB12-II action.
The present study clearly demonstrated that HA suppressed CB12-II-activated NF-κB via CD44 in OA articular chondrocytes, leading to decreased MMP-13 production. HA could down-regulate the catabolic action of type II collagen fragments in osteoarthritic joints through the mechanism demonstrated in this study.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nuclear-factor-%ce%bab-activation-by-type-ii-collagen-peptide-in-osteoarthritic-chondrocytes-its-inhibition-by-hyaluronan-via-cd44/