TGF-β1/Smad3 Signaling Pathway Mediates T-2 Toxin-Induced Decrease of Type II Collagen in Cultured Rat Chondrocytes

Li, Yang; Zhang, Ning; Wang, Jing; Wang, Kewei; Li, Fuyuan; Chen, Fu-Xun; Sun, Bingyu; Sun, Dianjun

doi:10.3390/toxins9110359

Cited by 16 publications

(10 citation statements)

References 23 publications

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“…Interestingly, T-2 toxin reduced the expression of type II collagen while promoting the expression of MMP13 through the activation of SMAD3 and the stimulation of TGF-β1 signaling, which ultimately led to chondrocyte damage. Chondrocytes undergo abnormal terminal differentiation, which is another pathogenic characteristic of KBD ( Li et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Ning

Diao

et al. 2022

Front. Genet.

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The mechanism of environmental factors in Kashin–Beck disease (KBD) remains unknown. We aimed to identify single nucleotide polymorphisms (SNPs) and protein alterations of selenium- and T-2 toxin–responsive genes to provide new evidence of chondrocytic damage in KBD. This study sampled the cubital venous blood of 258 subjects including 129 sex-matched KBD patients and 129 healthy controls for SNP detection. We applied an additive model, a dominant model, and a recessive model to identify significant SNPs. We then used the Comparative Toxicogenomics Database (CTD) to select selenium- and T-2 toxin–responsive genes with the candidate SNP loci. Finally, immunohistochemistry was applied to verify the protein expression of candidate genes in knee cartilage obtained from 15 subjects including 5 KBD, 5 osteoarthritis (OA), and 5 healthy controls. Forty-nine SNPs were genotyped in the current study. The C allele of rs6494629 was less frequent in KBD than in the controls (OR = 0.63, p = 0.011). Based on the CTD database, PPARG, ADAM12, IL6, SMAD3, and TIMP2 were identified to interact with selenium, sodium selenite, and T-2 toxin. KBD was found to be significantly associated with rs12629751 of PPARG (additive model: OR = 0.46, p = 0.012; dominant model: OR = 0.45, p = 0.049; recessive model: OR = 0.18, p = 0.018), rs1871054 of ADAM12 (dominant model: OR = 2.19, p = 0.022), rs1800796 of IL6 (dominant model: OR = 0.30, p = 0.003), rs6494629 of SMAD3 (additive model: OR = 0.65, p = 0.019; dominant model: OR = 0.52, p = 0.012), and rs4789936 of TIMP2 (recessive model: OR = 5.90, p = 0.024). Immunohistochemistry verified significantly upregulated PPARG, ADAM12, SMAD3, and TIMP2 in KBD compared with OA and normal controls (p < 0.05). Genetic polymorphisms of PPARG, ADAM12, SMAD3, and TIMP2 may contribute to the risk of KBD. These genes could promote the pathogenesis of KBD by disturbing ECM homeostasis.

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Section: Discussionmentioning

confidence: 99%

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Ning

Diao

et al. 2022

Front. Genet.

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“…Previously published studies have shown that TGF-β signaling is closely associated with the activity of SYK, and the kinase activity of SYK is essential for the activation of some signaling receptor downstream effector molecules [25]. Upregulation and phosphorylation of SYK are important pathways for activation of the TGF-β1 signaling pathway [31]. The SYK inhibitor R406 has been shown to down-regulate inflammation through regulation of TGF-β1 signaling in an in vitro model of Pseudomonas aeruginosa infection [32].…”

Section: Discussionmentioning

confidence: 99%

Spleen Tyrosine Kinase (SYK) in the Progression of Peritoneal Fibrosis Through Activation of the TGF-β1/Smad3 Signaling Pathway

et al. 2019

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BackgroundLong-term exposure to hypertonic and high glucose in peritoneal dialysis fluid can result in peritoneal fibrosis. Spleen tyrosine kinase (SYK) has a role in inflammation and fibrosis. This study aimed to investigate the role of SYK in an in vivo rat model of peritoneal fibrosis and in rat peritoneal mesothelial cells (PMCs) in vitro and to investigate the underlying mechanisms.Material/MethodsSprague-Dawley rats (N=24) were randomized into the sham control group (N=6); the peritoneal fibrosis group (N=6) treated with intraperitoneal chlorhexidine digluconate; the SYK inhibitor group (N=6), treated with chlorhexidine digluconate and fostamatinib; and the TGF-β inhibitor group (N=6), treated with chlorhexidine digluconate and LY2109761. The rat model underwent daily intraperitoneal injection with 0.5 ml of 0.1% chlorhexidine digluconate. Rat peritoneal mesothelial cells (PMCs) were cultured in vitro in high glucose. SYK expression was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Enzyme-linked immunosorbent assay (ELISA) and qRT-PCR measured inflammatory mediators. Transforming growth factor-β1 (TGF-β1) and Smad3 were detected by Western blot. Short hairpin RNA (shRNA) was used to target the SYK gene.ResultsSYK was upregulated in the rat model of peritoneal fibrosis and was induced rat PMCs cultured in high glucose. Knockdown of SYK and inhibition of TGF-β1 significantly reduced fibrosis and inflammation. Findings in the in vivo rat model confirmed that SYK mediated peritoneal fibrosis by regulating TGF-β1/Smad3 signaling.ConclusionsIn a rat model and in rat PMCs, expression of SYK increased peritoneal fibrosis through activation of the TGF-β1/Smad3 signaling pathway.

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“…In tissue engineering applications, T 3 has been shown to increase the expression and synthesis of type II collagen [24], and improve articular cartilage surface architecture [25]. As the metabolite of T-2 toxin, it would be reasonable to assume that the HT-2 toxin will share similarity with the T-2 toxin, which leads to cartilage destruction by the degradation of the extracellular matrix [26,27]. In another study, the T-2 toxin promoted aggrecanase-2 mRNA expression [28].…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Properties of HT-2 Toxin in Human Chondrocytes: Could T3 Inhibit Toxicity of HT-2?

Zhang

Shao

Zhang

et al. 2019

Toxins

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Thyroid hormone triiodothyronine (T3) plays an important role in coordinated endochondral ossification and hypertrophic differentiation of the growth plate, while aberrant thyroid hormone function appears to be related to skeletal malformations, osteoarthritis, and Kashin-Beck disease. The T-2 toxin, present extensively in cereal grains, and one of its main metabolites, HT-2 toxin, are hypothesized to be potential factors associated with hypertrophic chondrocyte-related osteochondropathy, known as the Kashin-Beck disease. In this study, we investigated the effects of T3 and HT-2 toxin on human chondrocytes. The immortalized human chondrocyte cell line, C-28/I2, was cultured in four different groups: controls, and cultures with T3, T3 plus HT-2 and HT-2 alone. Cytotoxicity was assessed using an MTT assay after 24-h-exposure. Quantitative RT-PCR was used to detect gene expression levels of collagen types II and X, aggrecan and runx2, and the differences in runx2 were confirmed with immunoblot analysis. T3 was only slightly cytotoxic, in contrast to the significant, dose-dependent cytotoxicity of HT-2 alone at concentrations ≥ 50 nM. T3, together with HT-2, significantly rescued the cytotoxic effect of HT-2. HT-2 induced significant increases in aggrecan and runx2 gene expression, while the hypertrophic differentiation marker, type X collagen, remained unchanged. Thus, T3 protected against HT-2 induced cytotoxicity, and HT-2 was an inducer of the pre-hypertrophic state of the chondrocytes.

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TGF-β1/Smad3 Signaling Pathway Mediates T-2 Toxin-Induced Decrease of Type II Collagen in Cultured Rat Chondrocytes

Cited by 16 publications

References 23 publications

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Spleen Tyrosine Kinase (SYK) in the Progression of Peritoneal Fibrosis Through Activation of the TGF-β1/Smad3 Signaling Pathway

Cytotoxic Properties of HT-2 Toxin in Human Chondrocytes: Could T3 Inhibit Toxicity of HT-2?

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