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Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.

Publication ,  Journal Article
Lee, W; Nims, RJ; Savadipour, A; Zhang, Q; Leddy, HA; Liu, F; McNulty, AL; Chen, Y; Guilak, F; Liedtke, WB
Published in: Proc Natl Acad Sci U S A
March 30, 2021

Osteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies [A. M. Valdes, T. D. Spector, Nat. Rev. Rheumatol. 7, 23-32 (2011)]. We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury [W. Lee et al., Proc. Natl. Acad. Sci. U.S.A. 111, E5114-E5122 (2014); W. Lee, F. Guilak, W. Liedtke, Curr. Top. Membr. 79, 263-273 (2017)]. We therefore asked whether interleukin-1-mediated inflammatory signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied. We found that interleukin-1α (IL-1α) up-regulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+ at baseline and in response to mechanical deformation. Elevated resting state Ca2+ in turn rarefied the F-actin cytoskeleton and amplified mechanically induced deformation microtrauma. As intracellular substrates of this OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α, we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximal PIEZO1 gene promoter. Taken together, these signaling and genetic reprogramming events represent a detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Up-Regulation
  • Sus scrofa
  • Promoter Regions, Genetic
  • Primary Cell Culture
  • Osteoarthritis
  • Mechanotransduction, Cellular
  • Ion Channels
  • Interleukin-1alpha
  • Humans
  • Gene Knockdown Techniques
 

Citation

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Lee, W., Nims, R. J., Savadipour, A., Zhang, Q., Leddy, H. A., Liu, F., … Liedtke, W. B. (2021). Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A, 118(13). https://doi.org/10.1073/pnas.2001611118
Lee, Whasil, Robert J. Nims, Alireza Savadipour, Qiaojuan Zhang, Holly A. Leddy, Fang Liu, Amy L. McNulty, Yong Chen, Farshid Guilak, and Wolfgang B. Liedtke. “Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.Proc Natl Acad Sci U S A 118, no. 13 (March 30, 2021). https://doi.org/10.1073/pnas.2001611118.
Lee W, Nims RJ, Savadipour A, Zhang Q, Leddy HA, Liu F, et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Lee, Whasil, et al. “Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.Proc Natl Acad Sci U S A, vol. 118, no. 13, Mar. 2021. Pubmed, doi:10.1073/pnas.2001611118.
Lee W, Nims RJ, Savadipour A, Zhang Q, Leddy HA, Liu F, McNulty AL, Chen Y, Guilak F, Liedtke WB. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A. 2021 Mar 30;118(13).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2021

Volume

118

Issue

13

Location

United States

Related Subject Headings

  • Up-Regulation
  • Sus scrofa
  • Promoter Regions, Genetic
  • Primary Cell Culture
  • Osteoarthritis
  • Mechanotransduction, Cellular
  • Ion Channels
  • Interleukin-1alpha
  • Humans
  • Gene Knockdown Techniques