Isoliquiritigenin blunts osteoarthritis by inhibition of bone resorption and angiogenesis in subchondral bone

Baochao Ji,Hairong Ma,Li Cao,Zhendong Zhang,Wentao Guo,Abdusami Amat,Boyong Xu,Wenbo Mu

doi:10.1038/s41598-018-19162-y

Abstract

Isoliquiritigenin (ISL), a natural flavonoid extracted from licorice, has been demonstrated to exert attenuation of osteoclastogenesis and anti-angiogenesis activity in a wide variety of cells. Here, we first evaluated the effects of ISL on pathogenesis of osteoarthritis in a mouse model of OA. The data showed that ISL blunted progression of OA and lowered the Osteoarthritis Research Society International (OARSI)-Modified Making Score and protected the articular cartilage. The thickness of calcified cartilage zone was significantly decreased in ISL-treated ACLT mice compared with vehicle group. ISL increased expression level of lubricin and decreased collagen X (Col X), matrix metalloproteinase-13 (MMP-13). Moreover, ISL reduced aberrant active subchondral bone remodelling, including lowered trabecular pattern factor (Tb.pf) and increased bone volume/tissue volume (BV/TV, %) and thickness of subchondral bone plate (SBP) compared with vehicle-treated group. The results of immunostaining further revealed that ISL directly reduced RANKL-RANK-TRAF6 singling pathway induced osteoclastogenesis, prevented abnormal bone formation through indirect inhibition of TGF-β release. Additionally, ISL exerts anti-angiogenesis effects in subchondral bone through direct suppression of MMP-2. These results indicated that ISL attenuates progression of OA by inhibition of bone resorption and angiogenesis in subchondral bone, indicating that this may be a potential preventive therapy for OA.

Highlights

Osteoarthritis (OA) is the most frequent and costly form of arthritis, characterized by slowly, progressive, degenerative disorder confined to diarthrodial joints
Abnormal expression of matrix metalloproteinase-13 (MMP-13) and collagen X (Col X) were found in vehicle group compared with the sham control group, which was normalised by administrating ISL as assessed by immunostaining (Fig. 2B,E,F)
We have found that ISL blunted mechanically induced OA in mice by inhibition of receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK-TRAF6-induced osteoclastogenesis, excessive TGF-β release and angiogenesis in subchondral bone

Summary

Introduction

Osteoarthritis (OA) is the most frequent and costly form of arthritis, characterized by slowly, progressive, degenerative disorder confined to diarthrodial joints. The disease causes loss of articular cartilage and involves the entire joint including inflammation of synovium, formation of osteophyte, sclerosis of subchondral bone[1,2]. Isoliquiritigenin (ISL) (Fig. 1), a natural flavonoid extracted from licorice, has drawn wide attention due to its lots of biologic activities, including anti-diabetic, anti-cancer, anti-oxidant as well as anti-inflammatory properties and its proven pharmacologic safety[22,23,24]. A search of Medline, PubMed, and Medscape revealed no article on the subject of ISL for treatment of OA In this situation, we investigated whether ISL has potential effect for preventive treatment of OA, including delaying articular cartilage degeneration and subchondral bone sclerosis in mice anterior cruciate ligament transection (ACLT) models by inhibiting osteoclastogenesis, TGF-β-dependent Smad2/3 phosphorylation and angiogenesis

Methods

Results

Conclusion