CELLULAR SIGNALLING
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2025
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IF 3.7
Yuyan Sun,Ziyu Luo,Haiqi Zhou,Sha Wu,Hongwei Shen,Yuanyuan Fu,Thai Namanh Ngo,Wen Wang,Yuanrong Wang,Ying Kong
Chondrocyte mechanotransduction dysfunction is a key feature of osteoarthritis (OA). Previous studies have demonstrated that primary cilia play a crucial role in chondrocyte mechanosensation and signal transduction. Transient Receptor Potential Vanilloid 4(TRPV4), which is highly expressed on primary cilia, is a critical mechanotransduction protein and one of the most important Ca 2+ channels. However, the interplay between the mechanism of primary cilia-mediated signaling and that of TRPV4 channel regulation remains poorly understood. Here, we demonstrate that OA chondrocytes and Intraflagellar Transport Protein 88(Ift88) conditional knockout (cKO) mice exhibit reduced ciliary incidence. This results in cartilage degeneration. TRPV4 expression inversely correlated with ciliary integrity, increasing as cilia were lost. In cilia-intact healthy chondrocytes, TRPV4 antagonism inhibited Ca 2+ -dependent NF-κB activation while promoting type II collagen(COL2) synthesis. These effects were abolished by Interleukin-1 beta(IL-1β)-induced ciliary defect or IFT88 deficiency. Chromatin immunoprecipitation(ChIP) analysis revealed disrupted p65 binding to the COL2 promoter upon the loss of ciliary integrity. Crucially, Ift88 cKO chondrocytes showed unresponsive of the TRPV4 channel, as confirmed by Ca 2+ flux and changes in the expression levels of NF-κB and COL2. Our findings position primary cilia as indispensable regulators of TRPV4-mediated NF-κB - COL2 signaling, offering mechanistic insights into OA pathogenesis and identifying IFT88 as a therapeutic checkpoint.
研究领域:
分子生物学
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细胞生物学
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骨关节炎病理学
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信号转导
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转化医学
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软骨生物学
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机械生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 42
·
IF 11.7
Xulong Liu,Shangtong Jiang,Ting Jiang,Ziyang Lan,Xin Zhang,Zhenyu Zhong,Xiaodan Wu,Cunjing Xu,Yingying Du,Shengmin Zhang
Cartilage regeneration relies on adequate and continuous bioenergy supply to facilitate cellular differentiation and extracellular matrix synthesis. Chondrocytes frequently undergo energy stress under pathological conditions, characterized by disrupted cellular metabolism and reduced adenosine triphosphate (ATP) levels. However, there has limited progress in modulating energy metabolism for cartilage regeneration thus far. Here, we developed bioenergetic-active exosomes (Suc-EXO) to promote cartilage regeneration and homeostasis maintenance. Suc-EXO exhibited a 5.42-fold increase in ATP content, enabling the manipulation of cellular energy metabolism by fueling the TCA cycle. With continuous energy supply, Suc-EXO promoted BMSC chondrogenic differentiation via the P2X7-mediated PI3K-AKT pathway. Moreover, Suc-EXO improved chondrocyte anabolism and mitochondrial homeostasis via the P2X7-mediated SIRT3 pathway. In a rabbit cartilage defect model, the Suc-EXO–encapsulated hydrogel notably promoted cartilage regeneration and maintained neocartilage homeostasis, leading to 2.26 and 1.53 times increase in Col2 and ACAN abundance, respectively. These findings make a remarkable breakthrough in modulating energy metabolism for cartilage regeneration, offering immense potential for clinical translation.
研究领域:
再生医学
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细胞代谢
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组织工程
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Min Qiu,Liangyan Cheng,Jianbo Xu,Minwei Jin,Wenhua Yuan,Qinwen Ge,Kaiao Zou,Jiali Chen,Yuliang Huang,Ju Li,Liming Zhu,Bing Xu,Chunchun Zhang,Hongting Jin,Pinger Wang
Aims The main pathological features of osteoarthritis (OA) include the degeneration of articular cartilage and a decrease in matrix synthesis. Chondrocytes, which contribute to matrix synthesis, play a crucial role in the development of OA. Liquiritin, an effective ingredient extracted from Glycyrrhiza uralensis Fisch., has been used for over 1000 years to treat OA. This study aims to investigate the impact of liquiritin on OA and its underlying mechanism. Materials and methods Gait and hot plate tests assessed mouse behavior, while Micro-CT and ABH/OG staining observed joint morphological changes. The TUNEL kit detected chondrocyte apoptosis. Western blot and immunofluorescence techniques determined the expression levels of cartilage metabolism markers COL2 and MMP13, as well as apoptosis markers caspase3, bcl2, P53, and PUMA. KEGG analysis and molecular docking technology were used to verify the relationship between liquiritin and P53. Key findings Liquiritin alleviated pain sensitivity and improved gait impairment in OA mice. Additionally, we found that liquiritin could increase COL2 levels and decrease MMP13 levels both in vivo and in vitro. Importantly, liquiritin reduced chondrocyte apoptosis induced by OA, through decreased expression of caspase3 expression and increased expression of bcl2 expression. Molecular docking revealed a strong binding affinity between liquiritin and P53. Both in vivo and in vitro studies demonstrated that liquiritin suppressed the expression of P53 and PUMA in cartilage. Significance This indicated that liquiritin may alleviate OA progression by inhibiting the P53/PUMA signaling pathway, suggesting that liquiritin is a potential strategy for the treatment of OA.
研究领域:
药理学
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骨科
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细胞生物学
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分子生物学
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生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
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