The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis.
Acta Biochim Biophys Sin (Shanghai)
; 55(5): 818-830, 2023 May 26.
Article
em En
| MEDLINE
| ID: mdl-37232576
ABSTRACT
Osteoarthritis (OA) is a degenerative or posttraumatic condition of the joints. In OA chondrocytes, Nrf2 functions as a stress response regulator with antioxidant and anti-inflammatory effects. This study aims to investigate the role of Nrf2 and its downstream pathway in the development of osteoarthritis. IL-1ß treatment suppresses Nrf2, aggrecan, and COL2A1 levels and cell viability but promotes apoptosis in chondrocytes. IL-1ß stimulation induces cell apoptosis, upregulates the mRNA expression of inflammatory factors, decreases aggrecan, COL2A1, and Bcl-2 levels but increases ADAMTS-5, ADAMTS-4, MMP13, cleaved caspase 3, and BAX levels, and promotes p65 phosphorylation. Nrf2 overexpression exerts opposite effects on IL-1ß-treated chondrocytes, as demonstrated by the significant attenuation of IL-1ß-induced changes in chondrocytes. By binding to the HMGB1 promoter region, Nrf2 suppresses HMGB1 expression. Similar to Nrf2 overexpression, HMGB1 knockdown also attenuates IL-1ß-induced changes in chondrocytes. Notably, under IL-1ß stimulation, the effects of Nrf2 overexpression or tert-butylhydroquinone (TBHQ, an activator of Nrf2) on apoptosis, inflammatory factor expression, ECM and apoptosis, and NF-κB pathway activity in chondrocytes are remarkably reversed by HMGB1 overexpression or recombinant HMGB1 (rHMGB1). Similarly, rHMGB1 could partially counteract the curative effect of TBHQ on OA damage in mice. In OA cartilage tissue samples, the level of Nrf2 is lower, while the levels of HMGB1, apoptotic, and inflammatory factors are increased compared to normal cartilage tissue samples. In conclusion, for the first time, the Nrf2/HMGB1 axis was found to modulate apoptosis, ECM degradation, inflammation and activation of NF-κB signaling in chondrocytes and OA mice.
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MEDLINE
Assunto principal:
Osteoartrite
/
Proteína HMGB1
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article