Kartogenin inhibits pain behavior, chondrocyte inflammation, and attenuates osteoarthritis progression in mice through induction of IL-10

Ji Ye Kwon,Chang-Yong Lee,Sung-Hwan Park,Mi-La Cho,Jeongwon Choi,Seok Jung Kim,Hyun-Sik Na,Dong-Yun Shin,Seung Hoon Lee,Kyungah Jung,Keun Hyung Cho

doi:10.1038/s41598-018-32206-7

Abstract

Osteoarthritis (OA) is a major degenerative joint condition that causes articular cartilage destruction. It was recently found that enhancement of chondroclasts and suppression in Treg cell differentiation are involved in the pathogenesis of OA. Kartogenin (KGN) is a small drug-like molecule that induces chondrogenesis in mesenchymal stem cells (MSCs). This study aimed to identify whether KGN can enhance severe pain behavior and improve cartilage repair in OA rat model. Induction of OA model was loaded by IA-injection of MIA. In the OA rat model, treatment an intra-articular injection of KGN. Pain levels were evaluated by analyzing PWL and PWT response in animals. Histological analysis and micro-CT images of femurs were used to analyze cartilage destruction. Gene expression was measured by real-time PCR. Immunohistochemistry was analyzed to detect protein expression. KGN injection significantly decreased pain severity and joint destruction in the MIA-induced OA model. KGN also increased mRNA levels of the anti-inflammatory cytokine IL-10 in OA patients’ chondrocytes stimulated by IL-1β. Decreased chondroclast expression, and increased Treg cell expression. KGN revealed therapeutic activity with the potential to reduce pain and improve cartilage destruction. Thus, KGN could be a therapeutic molecule for OA that inhibits cartilage damage.

Highlights

Osteoarthritis (OA) is an articular degenerative disease, characterized by chronic pain, joint inflammation, and movement limitations
The small molecule KGN has been studied in chondrogenesis and cartilage tissue repair, there is little proof of the beneficial function of KGN the osteoarthritis-reported medical state
We demonstrated suppression of pro-inflammatory cytokine expression and chondroclast inhibition mediated by KGN in an experimental OA rat model

Summary

Introduction

Osteoarthritis (OA) is an articular degenerative disease, characterized by chronic pain, joint inflammation, and movement limitations. It is well reported that the expression of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 increases in OA articular cartilage or synovial fluid[8,9]. Cell differentiation and IL-10 levels were reduced significantly in peripheral blood or synovial fluid from OA patients compared to healthy controls or rheumatoid arthritis patients[10]. Intra-articular (IA) injection of KGN showed cartilage regeneration in a mouse OA model, KGN has not been studied to improve OA through the inhibition of osteoclastogenesis and upregulation of Treg cell differentiation and IL-10 levels. We injected KGN intra-articularly into experimental OA in vivo models to investigate whether the therapeutic activity of KGN would reduce cartilage destruction and joint inflammation. We conducted in vitro experiments to determine whether KGN could inhibit osteoclastogenesis and induce Treg cell differentiation

Objectives

Methods

Results

Conclusion