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

Abstract

Background Silymarin (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. Methods The 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. Results High-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. Conclusion SMN regulates the chondrocyte phenotype through Sirt1 and SOX9 to improve ECM homeostasis and may serve as a complementary therapy for early-stage knee OA.

Sirtuin 1 Induces Choroidal Neovascularization and Triggers Age-Related Macular Degeneration by Promoting LCN2 through SOX9 Deacetylation

“…These studies suggest that SIRT1 is not necessarily protective in AMD and is more likely to be two-sided. Previous studies have revealed that SIRT1 acts as a deacetylase with many downstream substrates, such as p65 NF- κ B [ 40 ], STAT3 [ 41 ], and CHK2 [ 42 ], SOX9 [ 43 ], and plays different roles in various biological processes mainly for deacetylation of histones and nonhistones with different mechanisms of action. Thus, the substrates regulated by SIRT1 deacetylation are all transcription factors, and the regulation of target genes by transcription factors is strongly dependent on the cellular and disease environment.…”

The protective activity of natural flavonoids against osteoarthritis by targeting NF-κB signaling pathway

“…Chondrocyte senescence can be regulated by IL-1β. Silymarin has been shown to improve IL-1β-stimulated cell senescence, decrease catabolic gene expression, and restore chondrogenic phenotype factor expression ( 130 ). The senescence-associated secretory phenotype (SASP) is associated with the biological actions of senescent cells in producing inflammation-promoting factors.…”

Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions

“…218,219 Silymarin has the ability to increase hepatic SIRT1 expression. 220 Silymarin can also increase SIRT1 expression in other tissues, such as hippocampus, 221 articular chondrocytes, 222 and heart muscle. 223 Silymarin seems to act differently in tumors: in lung cancer cells SIRT downregulated SIRT1 and exerted multiple antitumor effects such as reduced adhesion and migration and increased apoptosis.…”