A small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development

Yuanyuan Shi,Peng Yang,Zong Li,Fengyuan Zhao,Xin Zhang,Xiaoning Duan,Xin Fu,Weili Shi,Jianquan Wang,Zhenlong Liu,Qiang Liu,Jin Cheng,Xiaoqing Hu,Bo Ren,Huilei Yu,Jiying Zhang,Yingfang Ao

doi:10.1038/s41467-019-09839-x

Abstract

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.

Highlights

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists
To illustrate the chondrogenic potential of the selected compounds, COL2A1 and ACAN mRNA levels in human OA chondrocytes were examined after incubation with the above agents
We reported a candidate of disease-modifying OA drugs (DMOADs), BNTA, which significantly enhanced anabolic metabolism in OA chondrocytes, and rescued the decrease of main ECM structural molecules, such as type II collagen and ACAN, in OA cartilage explants and OA cartilage tissue developed by anterior cruciate ligament transection (ACLT) in rats

Summary

Introduction

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis. In this study, we aim to determine (1) whether the found agent can promote cartilage ECM structure generation, and if so, (2) whether SOD3 is the molecular target of BNTA and upregulation of SOD3 in chondrocytes stimulates cartilage ECM synthesis

Objectives

Methods

Results

Conclusion