Activation of p38 Mitogen-Activated Protein Kinase Is Inhibited by Hyaluronan via Intercellular Adhesion Molecule-1 in Articular Chondrocytes Stimulated With Type II Collagen Peptide

Abstract

Abstract. This study examined the activation of p38 mitogen-activated protein kinase with matrix metalloproteinase-13 (MMP-13) production by a synthetic peptide derived from type II collagen (CB12-II) and its inhibition by high molecular weight hyaluronan (HA) in chondrocytes. When cartilage explants or isolated chondrocytes in monolayer were incubated with CB12-II, the peptide (50 μM, 72 h) activated p38 in association with enhanced MMP-13 production. Inhibition studies with SB203580 (0.1 -1 μM) indicated the requirement of p38 for CB12-II-induced MMP-13 production. Pretreatment with 2700 kDa HA (1 mg/ml, 1 h) resulted in significant suppression of CB12-II-stimulated MMP-13 production in cartilage as well as in chondrocyte monolayer cultures. HA (1 mg/ml) suppressed p38 activation by CB12-II, leading to a decrease in MMP-13 production. The antibody (20 μg/ml) to intercellular adhesion molecule-1 (ICAM-1), which has been recognized as a receptor of HA on chondrocytes, reversed the HA effect on CB12-II action. Thus, the present study clearly demonstrated that high molecular weight HA suppressed CB12-IIactivated p38 via ICAM-1 in articular chondrocytes. HA could down-regulate the catabolic action of type II collagen fragments in osteoarthritic joints through the mechanism demonstrated in this study.

Type II collagen peptide stimulates Akt leading to nuclear factor-κB activation: Its inhibition by hyaluronan

“…In accordance with our previous studies (32,33), preincubation of chondrocytes with 2700 kDa HA at 1 mg/mL for 1 h significantly suppressed CB12-IIstimulated MMP-13 production (Fig. 2).…”

“…This synthetic peptide named CB12-II is derived from the CB12 fragment which is generated with cyanogen bromide cleavage of type II collagen, and corresponds to the residues 195-218 of bovine type II collagen. MMP-13 induction by CB12-II has been found to require activation of catabolic intracellular signaling pathways such as p38 mitogen-activated protein kinase (32) and nuclear factor (NF)-κB (33). Nuclear factor (NF)-κB, which consists of p50 and p65 subunits, is critical in the regulation of many genes including cytokines, chemokines, and adhesion molecules.…”

Hyaluronan Endocytosis: Mechanisms of Uptake and Biological Functions

“…Some receptors, such as CD44 and LYVE-1, serve dual purposes in that they not only facilitate the endocytosis of HA, but also trigger signaling events that generate cell specific responses to HA binding. ICAM-1 was initially believed to serve as a metabolic receptor for HA only but is now suspected to have cell signaling roles in response to HA binding [14,15].…”

“…Preliminary data suggests that ICAM-1 functions as a signaling molecule when HA binds to it. When HA is added to the macrophage cell line U937, it induces Akt phosphorylation which activates the nuclear factor-kappa B pathway, inducing interleukin-6 production, but blocking of ICAM-1 with an antibody stops this from occurring [14,15].…”

Injectable Hyaluronic Acid Drugs for the Treatment of Knee Osteoarthritis in the Context of Evidence-Based Medicine

“…Исследования in vitro демонстрируют, что препараты ГНК, так же как и эндогенная ГНК, способны блокировать этот механизм, конкурируя с фрагментами матрикса за связывание с вышеупомянутыми рецепторами [10][11][12]. Кроме того, ГНК может оказывать прямой противовоспалительный эффект, подавляя продукцию ИЛ1, ИЛ6 и ФНОα посредством других механизмов, в частности, увеличивая экспрессию ассоциированной с рецептором ИЛ1 киназы М и митоген-активированной протеинкиназы-фосфатазы 1 [13][14][15][16].…”