Adiponectin enhances intercellular adhesion molecule-1 expression and promotes monocyte adhesion in human synovial fibroblasts.

Hsien-Te Chen,Hsi-Kai Tsou,James Meng-Kun Shih,Yen-Jen Chen,Jui-Chieh Chen,Chih-Hsin Tang,Chuen-Mao Yang

doi:10.1371/journal.pone.0092741

Abstract

Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes and is involved in energy homeostasis. Adiponectin expression is significantly high in the synovial fluid of patients with osteoarthritis (OA). Intercellular adhesion molecule-1 (ICAM-1) is an important adhesion molecule that mediates monocyte adhesion and infiltration during OA pathogenesis. Adiponectin-induced expression of ICAM-1 in human OA synovial fibroblasts (OASFs) was examined by using qPCR, flow cytometry and western blotting. The intracellular signaling pathways were investigated by pretreated with inhibitors or transfection with siRNA. The monocyte THP-1 cell line was used for an adhesion assay with OASFs. Stimulation of OASFs with adiponectin induced ICAM-1 expression. Pretreatment with AMP-activated protein kinase (AMPK) inhibitors (AraA and compound C) or transfection with siRNA against AMPKα1 and two AMPK upstream activator- liver kinase B1 (LKB1) and calmodulin-dependent protein kinase II (CaMKII) diminished the adiponectin-induced ICAM-1 expression. Stimulation of OASFs with adiponectin increased phosphorylation of LKB1, CaMKII, AMPK, and c-Jun, resulting in c-Jun binding to AP-1 element of ICAM-1 promoter. In addition, adiponectin-induced activation of the LKB1/CaMKII, AMPK, and AP-1 pathway increased the adhesion of monocytes to the OASF monolayer. Our results suggest that adiponectin increases ICAM-1 expression in human OASFs via the LKB1/CaMKII, AMPK, c-Jun, and AP-1 signaling pathway. Adiponectin-induced ICAM-1 expression promoted the adhesion of monocytes to human OASFs. These findings may provide a better understanding of the pathogenesis of OA and can utilize this knowledge to design a new therapeutic strategy.

Highlights

Osteoarthritis (OA) is the most common chronic degenerative joint disorder in elderly individuals, which is often characterized by infiltration of inflammatory cells and production of multiple potent inflammatory mediators and matrix-degrading proteinases in synovium, leading to disabling pain, stiffness, cartilage breakdown, and a loss of joint function [1]
We initially assessed the effects of adiponectin on the expression of intercellular adhesion molecule-1 (ICAM-1) in human OA synovial fibroblasts (OASFs)
The treatment of OASFs with adiponectin resulted in a dose-dependent increase in mRNA and cell surface ICAM-1 expression, as assessed by quantitative real-time PCR (qPCR) (Fig. 1A) and flow cytometry (Fig. 1B)

Summary

Introduction

Osteoarthritis (OA) is the most common chronic degenerative joint disorder in elderly individuals, which is often characterized by infiltration of inflammatory cells and production of multiple potent inflammatory mediators and matrix-degrading proteinases in synovium, leading to disabling pain, stiffness, cartilage breakdown, and a loss of joint function [1]. Adiponectin receptors have been identified on the surface of synovial fibroblasts, which are necessary to exert the adiponectin-dependent signals to increase the production of cartilage-degrading matrix metalloproteinase (MMP) enzymes, cytokines and prostaglandin E2 [11,12,13]. Besides release of inflammatory mediators, infiltration of inflammatory cells has been detected in the inflamed synovium of OA patients, which plays a critical role in persistent inflammation and joint destruction [14]. The movement of mononuclear cells into the inflammatory sites is regulated by adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1)

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Discussion

Conclusion