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

Publication ,  Journal Article
O'Conor, CJ; Leddy, HA; Benefield, HC; Liedtke, WB; Guilak, F
Published in: Proc Natl Acad Sci U S A
January 28, 2014

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 Ca(2+)-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 Ca(2+) 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 Ca(2+) 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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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 28, 2014

Volume

111

Issue

4

Start / End Page

1316 / 1321

Location

United States

Related Subject Headings

  • TRPV Cation Channels
  • Swine
  • Sepharose
  • Mechanotransduction, Cellular
  • Gene Expression Regulation
  • Chondrocytes
  • Cells, Cultured
  • Animals
 

Citation

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O’Conor, C. J., Leddy, H. A., Benefield, H. C., Liedtke, W. B., & Guilak, F. (2014). TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A, 111(4), 1316–1321. https://doi.org/10.1073/pnas.1319569111
O’Conor, Christopher J., Holly A. Leddy, Halei C. Benefield, Wolfgang B. Liedtke, and Farshid Guilak. “TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.Proc Natl Acad Sci U S A 111, no. 4 (January 28, 2014): 1316–21. https://doi.org/10.1073/pnas.1319569111.
O’Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1316–21.
O’Conor, Christopher J., et al. “TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.Proc Natl Acad Sci U S A, vol. 111, no. 4, Jan. 2014, pp. 1316–21. Pubmed, doi:10.1073/pnas.1319569111.
O’Conor CJ, Leddy HA, Benefield HC, Liedtke WB, Guilak F. TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1316–1321.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 28, 2014

Volume

111

Issue

4

Start / End Page

1316 / 1321

Location

United States

Related Subject Headings

  • TRPV Cation Channels
  • Swine
  • Sepharose
  • Mechanotransduction, Cellular
  • Gene Expression Regulation
  • Chondrocytes
  • Cells, Cultured
  • Animals