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

Journal of Orthopaedic Surgery and Research

Wen-Tien Wu¹  Chen-Chie Wang²  Yi-Ru Chen³  Kai-Chiang Yang³  Fedor Svyatoslavovich Senatov⁴  Dai-Hua Lu⁵ 

[1] Department of Orthopedic Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Rd., Xindian Dist, 23142, New Taipei City, Taiwan;Department of Orthopedics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan;Department of Orthopedics, School of Medicine, Tzu Chi University, Hualien, Taiwan;Department of Orthopedic Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Rd., Xindian Dist, 23142, New Taipei City, Taiwan;Department of Orthopedics, School of Medicine, Tzu Chi University, Hualien, Taiwan;Department of Orthopedic Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Rd., Xindian Dist, 23142, New Taipei City, Taiwan;School of Dental Technology, College of Oral Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist, 11031, Taipei, Taiwan;Researcher of the Centre for Composite Materials, National University of Science and Technology MISIS, Moscow, Russia;School of Dental Technology, College of Oral Medicine, Taipei Medical University, No. 250, Wuxing St., Xinyi Dist, 11031, Taipei, Taiwan;

关键词: Osteoarthritis;    Catabolic cytokine;    Silymarin;    Matrix metalloproteinase;    Sirtuin-1;   

DOI  :  10.1186/s13018-021-02305-9

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY