Effects of Visfatin on Intracellular Mechanics and Catabolism in Human Primary Chondrocytes through Glycogen Synthase Kinase 3β Inactivation.

Shun-Fu Chang,Wei-Ru Lee,Yao-Chang Chiang,Kuo-Chin Huang,Yu-Ping Su,Shun-Chi Wu,Rong-Ze Hsieh,Kuan-Han Lee

doi:10.3390/ijms22158107

Abstract

Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3β (GSK3β) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3β inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.

Highlights

Osteoarthritis (OA) is the most common articular cartilage degeneration disease
Our results found that visfatin damages the microtubule and microfilament networks to affect intracellular mechanics, which decreases intracellular elasticity and viscosity properties in human primary chondrocytes through glycogen synthase kinase 3β (GSK3β) inactivation induced by p38 signaling; the microtubule network destruction in human primary chondrocytes is predominantly responsible for the visfatin catabolic effect on cyclooxygenase 2 (COX2) upregulation
Cells treated with 5 μg/mL of visfatin displayed the maximal induced level of COX2 expression compared to those treated with lower concentrations (Figure 1B)

Summary

Introduction

Osteoarthritis (OA) is the most common articular cartilage degeneration disease. The chondrocyte is the only type of cell in articular cartilage. Upon the onset of OA, an imbalanced metabolism in chondrocytes gradually results in a higher secretion of catabolic factors, e.g., matrix metalloprotease (MMP) and cyclooxygenase 2 (COX2), than those of the anabolic factors, e.g., collagen II and aggrecan. This means that the degradation rate in cartilage becomes gradually higher than the regeneration and repair rate, which leads to cartilage destruction [1,2]. Increase of COX2 expression/activity has been indicated as a catabolic event in chondrocytes [3]

Methods

Results

Conclusion