ATHEROSCLEROSIS
·
2025
·
IF 5.7
Zhenyu Zhu,Hao Liu,Liyun Feng,Lihe Lu,Jiahui Zhu,Qingchun Liang,Zirong Lan,Yuanzhi Ye,Siyi Wang,An Chen,Jianyun Yan
Introduction Extracellular matrix (ECM) proteases have been closely linked to the pathogenesis of vascular calcification. A disintegrin and metalloprotease with thrombospondin motifs-5 (ADAMTS5) is an ECM-degrading enzyme involved in ECM remodeling. Versican, a critical ECM component in the arteries, can be proteolytically cleaved by ADAMTS5 and activates integrin β1. However, whether ADAMTS5 is involved in the regulation of the pathogenesis of vascular calcification remains unclear. This study investigates the regulatory role of ADAMTS5 in vascular calcification and its mechanistic link to versican-integrin β1/FAK signaling. Methods and results Western blot, immunofluorescence, and immunohistochemistry analysis revealed that ADAMTS5 expression was significantly downregulated in rat and human vascular smooth muscle cells (VSMCs), as well as in rat and human arteries during vascular calcification. In addition, both pharmacological inhibition of ADAMTS5 and knockdown of ADAMTS5 by siRNA significantly aggravated mineral deposition in rat and human VSMCs under osteogenic conditions. Moreover, adenovirus-mediated ADAMTS5 overexpression markedly attenuated calcification of VSMCs and aortic calcification in rats with chronic kidney disease. Furthermore, inhibition of ADAMTS5 promoted aortic calcification in VitD 3 -overloaded mice. Mechanistically, overexpression of ADAMTS5 significantly reduced versican protein levels, and inhibited integrin β1 and FAK phosphorylation in rat VSMCs, but increased versikine protein levels. Moreover, either knockdown of versican or pharmacological inhibition of FAK phosphorylation repressed VSMC calcification mediated by loss of ADAMTS5. Conclusions We have demonstrated for the first time that ADAMTS5 deficiency promotes versican accumulation and activates integrin β1/FAK signaling. These findings suggest ADAMTS5 as a potential therapeutic target for vascular calcification.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Shang JingJing,Xiong Chenwei,Jiang Wei,Yu Zhentang,Zhang Junjie,Zhang Yi,Han Long,Miao Kaisong,Yu Changlin,Huang Yong,Zhou Xindie
Background: Osteoarthritis (OA) is a chronic joint disease, usually accompanied by degeneration
of the articular cartilage, fibrosis, bone hyperplasia around the joint, and damage to the
entire articular surface. Gossypol is a natural phenolic compound isolated from the seed of cotton
plants, and gossypol acetic acid (GAA) is a medicinal form of Gossypol. Recently, various biological
activities of GAA, including anti-inflammatory and anti-tumor effects, have been widely reported.
However, its effect on chondrocytes in OA has yet to be determined.
Methods: In this study, we investigated the effect of GAA on ferroptosis in OA chondrocytes. The
effect of GAA on the cell viability and cytotoxicity of chondrocytes in rat cells was investigated
using CCK8. Western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescence
staining were used to elucidate the molecular mechanisms and signaling pathways of GAA inhibition
of ferroptosis in OA chondrocytes. The effect of GAA on reactive oxygen species (ROS) production
and lipid peroxidation levels in chondrocytes was examined using dihydroethidium (DHE)
staining and fluorescent dye BODIPY581/591 C11. in vivo, micro-CT imaging, hematoxylin
and eosin staining, Safranin O-Fast staining, and immunohistochemistry were performed to evaluate
the effects of GAA on OA cartilage.
Results: The results showed that GAA treatment regulated the expression of chondrocyte extracellular
matrix (ECM) related factors, including ADAMTS5, MMP13, SOX9, Aggrecan, and
COL1A2 and reduced the ROS and lipid peroxidation levels. Besides, Erastin could reverse the effects
of GAA on chondrocytes. Similar to GAA, 5-AZA caused the reduction of ROS and lipid
peroxidation levels and reversed the effect of IL-1β on the expression of ECM-related factors in
OA chondrocytes. The above results clarified that GAA alleviated the ferroptosis of chondrocytes
in OA by inhibiting GPX4 methylation.
Conclusion: Our findings revealed that GAA might be developed as a drug for treating OA clinically.
研究领域:
药理学
·
骨科
·
细胞生物学
·
生物化学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Minjun Yao,Caihua Zhang,Lingzhi Ni,Xiaoxiao Ji,Jianqiao Hong,Yazhou Chen,Jie Wang,Congsun Li,Jiyan Lin,Tingting Lu,Yihao Sheng,Menghao Sun,Mingmin Shi,Chenhe Zhou,Xunzi Cai
Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha , exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.
研究领域:
药理学
·
风湿病学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
eLife
·
2021
·
IF 8.146
Fan Xue,Zhenlei Zhao,Yanpei Gu,Jianxin Han,Keqiang Ye,Ying Zhang
Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-Dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation, and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix, and osteoprotegerin (OPG) was all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation, and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties, and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.
研究领域:
药理学
·
骨生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）