2. Academic Validation
  3. Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes

Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes

  • Osteoarthritis Cartilage. 2023 May 7;S1063-4584(23)00776-8. doi: 10.1016/j.joca.2023.05.004.
E L Taylor 1,  J A Collins 2,  P Gopalakrishnan 1,  S Chubinskaya 3,  R F Loeser 4
Affiliations

Affiliations

  • 1 Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA.
  • 2 Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA; Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
  • 3 Department of Pediatrics, Rush Medical College, Chicago, IL, USA.
  • 4 Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: richard_loeser@med.unc.edu.
PMID: 37160250 DOI: 10.1016/j.joca.2023.05.004
Abstract

Objective: The purpose of this study was to investigate the effect of age and oxidative stress on regulation of Nrf2 in young, old, and osteoarthritic human articular chondrocytes.

Design: Levels of Nrf2 in primary human chondrocytes isolated from young, old, and OA donors were measured by immunoblotting, qPCR, and immunohistochemistry. Effects on levels of Nrf2, antioxidant proteins regulated by Nrf2, as well as p65, and the anabolic response to IGF-1 were evaluated after induction of oxidative stress with menadione, Nrf2 knockdown with siRNA, and/or Nrf2 activation with RTA-408.

Results: Nrf2 protein levels were significantly lower in older adult chondrocytes (~0.59 fold; p= 0.034) and OA chondrocytes (~0.50 fold; p=0.016) compared to younger cells. Menadione significantly increased Nrf2 protein levels in young chondrocytes by just under 4-fold without changes in old chondrocytes. Nrf2 knockdown and activation differentially regulated levels of anti-oxidant proteins including Srx and NQO1. Nrf2 activation with RTA-408 also decreased basal p65 phosphorylation, increased aggrecan and type II collagen gene expression, and increased production of proteoglycans in OA chondrocytes treated with IGF-1.

Conclusions: Targeted therapeutic strategies aimed at maintaining Nrf2 activity could be useful in maintaining chondrocyte homeostasis through maintenance of intracellular antioxidant function and redox balance.

Keywords

Aging; Chondrocytes; Nrf2; Osteoarthritis; Oxidative stress.

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