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PNAS:TRPV4离子通道激发软骨再生

2014-02-08 17:38  
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杜克大学在新研究中发现,软骨细胞通过TRPV4来感知机械负荷。这一发现进一步阐明软骨组织的再生机制。相关文章发表于2014年1月13日的《PNAS》杂志上。
PNAS:TRPV4离子通道激发软骨再生

PNAS:TRPV4离子通道激发软骨再生

众所周知,软骨很难生长和修复。日前,Duke大学医学院的研究人员进一步阐明了这一结缔组织的再生机制。他们的研究显示,向软骨细胞添加一种化合物,可以刺激新软骨的生长,模拟体育锻炼的效果。他们指出TRPV4离子通道可以成为潜在的药物靶点,帮助人们治疗关节炎甚至再生软骨组织。

膝盖、肩膀等关节处的软骨组织,可以起到缓冲的作用,使肢体动作流畅进行。体育锻炼可以使软骨保持健康和强壮,这一点类似于骨骼和肌肉。

关节处的异常受力会引起许多问题,导致疼痛甚至使人丧失行动能力。过度使用或者外伤会使软骨组织受损,而运动过少会令软骨发生萎缩。上述两种情况都很容易引发关节炎。

此前,人们还不清楚软骨如何将机械负荷转化为促进生长的信号。而理解这一机制可以帮助研究者们更好地预防和治疗关节疾病。

“机械负荷对于软骨的健康很关键,”文章的资深作者,Farshid Guilak教授说。“如果我们能了解软骨细胞感知机械负荷的机制,就可以对其加以利用,并在此基础上治疗相应的关节疾病。”

研究人员针对TRPV4研究了猪关节处的软骨细胞,TRPV4是一种在软骨细胞里含量丰富的离子通道,这种通道能够在机械负荷时开启。研究人员为软骨细胞创造了机械负荷条件,使细胞生长了新的软骨组织。随后,他们向细胞中添加能阻断TRPV4的化合物,关闭了该离子通道的信号,结果是软骨不再生长,机械负荷的效果消失。

研究人员还发现,能激活TRPV4的物质可以取代机械负荷。研究显示,与机械负荷条件相比,添加激活物时软骨生长更多。这说明,软骨细胞通过TRPV4来感知机械负荷。

由于激活TRPV4能够在软骨细胞中起到机械负荷的效果,研究人员正在想办法利用这一机制。

“我们的下一步是,研究这一机制是否适用于人类细胞,促进人类软骨的再生,”文章的第一作者Christopher O'Conor说。研究人员希望通过激活或阻断TRPV4,开发新药来抑制软骨退化和治疗关节疾病。

原文摘要:

TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading

C. J. O'Conor, H. A. Leddy, H. C. Benefield, W. B. Liedtke, F. Guilak

Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable osmomechano-TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca2+ signaling in agarose-embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loading-induced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca2+ signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation.

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