Journal Article

Cannabinoid WIN-55,212-2 mesylate inhibits ADAMTS-4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan-1

KONG, YING, WANG, WANCHUN, ZHANG, CHANGJIE, WU, YI, LIU, YANG, ZHOU, XIAORONG

2016

Overview

A central feature of osteoarthritis (OA) is the loss of articular cartilage, which is primarily attributed to cartilage breakdown. A group of metalloproteinases termed the A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family are reported to be important in cartilage breakdown. Recent studies have suggested that ADAMTS-4 is a major contributor to the pathogenesis of OA and that syndecan-1 is closely associated with activation of ADAMTS-4 in human chondrocytes. Accumulating evidence also suggests that cannabinoids have chondroprotective effects. The current study explored the effects of synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55) on the expression of syndecan-1 and ADAMTS-4, as well as ADAMTS-4 activity, in unstimulated and interleukin (IL)-1β-stimulated OA chondrocytes. Primary human OA articular chondrocytes were treated with WIN-55 in the presence or absence of IL-1β and cannabinoid receptor antagonists. The results of the present study demonstrated that WIN-55 inhibited ADAMTS-4 activity in unstimulated and IL-1β-stimulated primary human OA articular chondrocytes in a concentration-dependent manner. Cannabinoid receptor type 1 (CB1) and 2 (CB2) were constitutively expressed in human OA articular chondrocytes. Furthermore, selective CB2 antagonist, JTE907, but not selective CB1 antagonist, MJ15, abolished the inhibitory effect of WIN-55 on ADAMTS-4 activity. WIN55 inhibited the expression of syndecan-1 but not ADAMTS-4, and overexpression of syndecan-1 reversed the inhibitory effect of WIN-55 on the ADAMTS-4 activity in unstimulated and IL-1β-stimulated human OA articular chondrocytes. Despite having no significant effect on syndecan-1 gene promoter activity, WIN-55 markedly decreased the stability of syndecan-1 mRNA via CB2. In conclusion, to the best of our knowledge, the present study provides the first in vitro evidence supporting that the synthetic cannabinoid WIN-55 inhibits ADAMTS-4 activity in unstimulated and IL-1β-stimulated human OA articular chondrocytes by decreasing the mRNA stability/expression of syndecan-1 via CB2. This suggests a novel mechanism by which cannabinoids may prevent cartilage breakdown in OA. In addition, it also provides novel insights into the pharmacological effects of synthetic cannabinoids on OA.

• Publisher: D.A. Spandidos,Spandidos Publications,Spandidos Publications UK Ltd
• Subject: 212-2 mesylate / A disintegrin-like and metallopeptidase with thrombospondin motifs-4 / ADAM protein / ADAMTS4 Protein - antagonists & inhibitors / Arthritis / Benzoxazines - pharmacology / cannabinoid / Cannabinoid CB1 receptors / Cannabinoid CB2 receptors / cannabinoid receptor type 2 / Care and treatment / Cartilage (articular) / Cartilage diseases / Cartilage, Articular - metabolism / Cartilage, Articular - pathology / Cells, Cultured / chondrocyte / Chondrocytes / Chondrocytes - drug effects / Chondrocytes - metabolism / Cytokines / Development and progression / Enzyme Activation - drug effects / Extracellular matrix / Fluorides / Gene expression / Gene Expression Regulation - drug effects / Genetic aspects / Growth factors / Health aspects / Humans / IL-1β / Interleukin-1beta - metabolism / Interleukin-1beta - pharmacology / Laboratories / Membrane proteins / Morpholines - pharmacology / mRNA stability / Naphthalenes - pharmacology / Osteoarthritis / Osteoarthritis - genetics / Osteoarthritis - metabolism / Osteoarthritis - pathology / Polyclonal antibodies / Properties / Proteases / Proteins / Receptor, Cannabinoid, CB2 - metabolism / Signal Transduction - drug effects / Studies / Syndecan / syndecan-1 / Syndecan-1 - genetics / Thrombospondin / Tumor necrosis factor-TNF / WIN-55