Silymarin modulates catabolic cytokine expression through Sirt1 and SOX9 in human articular chondrocytes

Wen-Tien Wu,Dai-Hua Lu,Yi-Ru Chen,Fedor Svyatoslavovich Senatov,Chen-Chie Wang,Kai-Chiang Yang

doi:10.1186/s13018-021-02305-9

Abstract

BackgroundSilymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including anti-inflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNF-α) stimulation in a chondrocyte cell line. However, pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated.MethodsThe cytotoxicity of SMN (12.5, 25, 50 and 100 μM) was evaluated in human primary chondrocytes. The chondrocytes were supplemented with SMN (25 and 50 μM) after interleukin-1beta (IL-1β) stimulation. The mRNA expression and protein production of catabolic/anabolic cytokines as well as extracellular matrix (ECM) components were evaluated.ResultsHigh-dose SMN (100 μM) impaired the mitochondrial activity in chondrocytes, and 50 μM SMN further caused cell death in IL-1β-stimulated cells. The addition of 25 μM SMN ameliorated cell senescence; downregulated the catabolic genes of inducible nitric oxide synthase, IL-1β, TNF-α, matrix metalloproteinase-3 (MMP-3), MMP-9 and MMP-13; upregulated the anabolic genes of tissue inhibitor of metalloproteinase-1 (TIMP-1) and collagen type II alpha 1; and restored the expression of chondrogenic phenotype genes SOX9 and sirtuin-1 (Sirt1). In addition, the production of IL-1β, MMP-3 and MMP-9 decreased with an increase in TIMP-1 secretion. However, the mRNA levels of IL-6, IL-8 and IL-10 and protein production remained high. The addition of nicotinamide, a Sirt1 inhibitor, downregulated SOX9 and attenuated the therapeutic effects of SMN on IL-1β-stimulated chondrocytes.ConclusionSMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA.

Highlights

Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including antiinflammation
Disturbances in extracellular matrix (ECM) anabolism and catabolism are triggered by metabolic inflammation and oxidative stress and are known to initiate knee osteoarthritis (OA)-related pathological changes [1]
In a monoiodoacetate-induced rat OA model, SMN enhanced the anti-inflammatory activity of the nonsteroidal anti-inflammatory drug (NSAID) celecoxib [11]

Summary

Introduction

Silymarin (SMN), a polyphenolic flavonoid, is involved in multiple bioactive functions including antiinflammation. Pretreatment with SMN demonstrated chondroprotection against tumour necrosis factor-alpha (TNFα) stimulation in a chondrocyte cell line. Pre- and posttreatment with phytochemicals have varying effects on osteoarthritis (OA) chondrocytes, and the therapeutic potential of SMN after catabolic cytokine stimulation is not fully elucidated. Interventions to modulate ECM homeostasis as well as to enhance the anti-inflammatory and antioxidant activities of articular chondrocytes are a promising therapeutic strategy against OA in the early stages [4]. Silymarin (SMN), a polyphenolic flavonoid, exerts anticarcinogenic, anti-inflammatory, cytoprotective and antioxidant effects, as evident in its radical scavenging activities, by regulating various cell membrane and nuclear transporters [6]. SMN pretreatment before tumour necrosis factor alpha (TNF-α) exposure exerted chondroprotection through the modulation of interleukin 6 (IL-6), IL-8 and MMP-1 mRNA expression in human chondrocyte cells [10]. Combination therapy with SMN reduced the adverse events of the NSAID celecoxib in an OA rat model [13]

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