Sustained Akt signaling in articular chondrocytes causes osteoarthritis via oxidative stress-induced senescence in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31646013.
- Also identified by DOI 10.1038/s41413-019-0062-y and PMC identifier 6804644.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Osteoarthritis (OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are unclear. In this study, we found activated Akt signaling in human OA cartilage as well as in a mouse OA model with surgical destabilization of the medial meniscus. Genetic mouse models mimicking sustained Akt signaling in articular chondrocytes via <i>PTEN</i> deficiency driven by either <i>Col2a1-Cre</i> or <i>Col2a1-Cre</i> <sup><i>ERT2</i></sup> developed OA, whereas restriction of Akt signaling reversed the OA phenotypes in <i>PTEN</i>-deficient mice. Mechanistically, prolonged activation of Akt signaling caused an accumulation of reactive oxygen species and triggered chondrocyte senescence as well as a senescence-associated secretory phenotype, whereas chronic administration of the antioxidant N-acetylcysteine suppressed chondrocyte senescence and mitigated OA progression in <i>PTEN</i>-deficient mice. Therefore, inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage. Disrupted Akt signaling in articular chondrocytes triggers oxidative stress-induced chondrocyte senescence and causes OA.