Physalin A Inhibits MAPK and NF-κB Signal Transduction Through Integrin αVβ3 and Exerts Chondroprotective Effect.

Rui Lu,Zhenggang Wang,Wen-Tao Zhu,Shuang Liang,Xiaojun Yu,Zhi-Yi He,Zheng-Tao Lv,Peng Cheng,Junlai Wan,An-Min Chen,Haokun Mo

doi:10.3389/fphar.2021.761922

Abstract

Osteoarthritis (OA) is a common articular ailment presented with cartilage loss and destruction that is common observed in the elderly population. Physalin A (PA), a natural bioactive withanolide, exerts anti-inflammatory residences in more than a few diseases; however, little is known about its efficacy for OA treatment. Here, we explored the therapeutic effects and potential mechanism of PA in mouse OA. After the in vitro administration of PA, the expression of inflammation indicators including inducible nitric oxide synthase and cyclooxygenase-2 was low, indicating that PA could alleviate the IL-1β-induced chondrocyte inflammation response. Moreover, PA reduced IL-1β-induced destruction of the extracellular matrix by upregulating the gene expression of anabolism factors, including collagen II, aggrecan, and sry-box transcription factor 9, and downregulating the gene expression of catabolic factors, including thrombospondin motif 5 and matrix metalloproteinases. In addition, the chondroprotective effect of PA was credited to the inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Furthermore, in vivo experiments showed that intra-articular injection of PA could alleviate cartilage destruction in a mouse OA model. However, the anti-inflammatory, anabolism enhancing, catabolism inhibiting, and MAPK and NF-κB signaling pathway inhibiting properties of PA on IL-1β-induced chondrocytes could be reversed when integrin αVβ3 is knocked down by siRNA. In conclusion, our work demonstrates that PA exhibits a chondroprotective effect that may be mediated by integrin αVβ3. Thus, PA or integrin αVβ3 might be a promising agent or molecular target for the treatment of OA.

Highlights

OA is the most common articular disorder in the world, affecting 9.6% of men and 18% of women over 60, and is characterized by cartilage damage, joint space narrowing, sclerosis or osteoporosis of the subchondral bone, formation of osteophytes, and synovial membrane inflammation, which occurs in weight-bearing joints and joints subjected to high levels of activity
We found that the inflammatory markers iNOS and COX2 were highly expressed in the Interleukin 1β (IL-1β)-treated group, and Physalin A (PA) restrained the production of these two proteins; the inhibitory effect of PA on chondrocytes could be reversed when integrin αVβ3 was knocked down (Figures 6E,F)
Previous research revealed that inflammatory factors play a major part in the process of OA progression, and the balance of pro-inflammatory and antiinflammatory cytokines is essential for maintaining the steady state of catabolism and anabolism in articular cartilage (Sellam and Berenbaum, 2010; Lee et al, 2021)

Summary

Introduction

OA is the most common articular disorder in the world, affecting 9.6% of men and 18% of women over 60, and is characterized by cartilage damage, joint space narrowing, sclerosis or osteoporosis of the subchondral bone, formation of osteophytes, and synovial membrane inflammation, which occurs in weight-bearing joints and joints subjected to high levels of activity. Physalin A for Osteoarthritis Treatment of the affected joint, and the pain and dysfunction caused by this disease are the most important factors impacting the lives of elderly people (Woolf and Pfleger, 2003). It is a degenerative disease influenced by aging, trauma, obesity, strain, joint deformity, and many other factors; the exact mechanism of OA remains unclear (Glyn-Jones et al, 2015; Jeon et al, 2017). These drugs and methods are not effective at reducing or reversing the symptoms of OA (Crowley et al, 2009)

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