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ERK1 loss accelerates the progression of osteoarthritis in aged mice via NRF2/BACH1 signaling
Jian Chen1, Zhijun Chen2, Putao Yuan2
1Department of Orthopaedic, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China; Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China.
Abstract:
Osteoarthritis (OA) is now a common degenerative joint related disease. However, the clinical efficacy of drugs associated with cartilage regeneration remains limited. In our study, we firstly explored the role of ERK1 in the progression of OA. We clarified that ERK1-deficient mice were susceptible to age-related OA. The higher OARSI scores and more severe cartilage degeneration was observed in the ERK1-deficient mice. ERK1 deficiency decreased the nuclear transportation of Nrf2 in the chondrocytes and accelerated chondrocyte aging in vitro. Moreover, chondrocytes with ERK1 deficiency elevated the nuclear expression of BACH1, resulting in lowered expression of antioxidant enzymes in ERK1-deficient chondrocytes. The Nrf2 activator dimethyl fumarate (DMF) was used. Our experiments demonstrated the protective function of DMF against OA in ERK1 knockout mice. Above all, we confirmed the effects of ERK1 on the progression of OA and clarified the mechanisms underlying these effects. DMF might has significant use in the development of novel drugs for the therapy of OA in the future.
Insights
Osteoarthritis (OA) progression is linked to ERK1 deficiency, which accelerates chondrocyte aging. The Nrf2 activator, dimethyl fumarate (DMF), showed protective effects against OA in mice.
Area of Science:
- Biomedical Science
- Molecular Biology
- Aging Research
Background:
- Osteoarthritis (OA) is a prevalent degenerative joint disease with limited therapeutic options for cartilage regeneration.
- The precise molecular mechanisms driving OA progression, particularly the role of specific signaling pathways, require further elucidation.
Purpose of the Study:
- To investigate the role of Extracellular signal-Regulated Kinase 1 (ERK1) in the development and progression of osteoarthritis.
- To elucidate the underlying molecular mechanisms by which ERK1 influences chondrocyte aging and OA pathogenesis.
- To evaluate the therapeutic potential of a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, dimethyl fumarate (DMF), in an OA model.
Main Methods:
- Utilized ERK1-deficient mice to assess susceptibility to age-related osteoarthritis and cartilage degeneration.
- Examined the impact of ERK1 deficiency on nuclear translocation of Nrf2 and chondrocyte aging in vitro.
- Investigated the expression of BACH1 and antioxidant enzymes in ERK1-deficient chondrocytes.
- Administered dimethyl fumarate (DMF) to ERK1 knockout mice to evaluate its protective effects against OA.
Main Results:
- ERK1-deficient mice exhibited increased susceptibility to age-related OA, characterized by higher OARSI scores and severe cartilage degeneration.
- ERK1 deficiency impaired nuclear transport of Nrf2 in chondrocytes and accelerated chondrocyte aging in vitro.
- ERK1 deficiency led to elevated nuclear expression of BACH1 and reduced antioxidant enzyme expression in chondrocytes.
- Treatment with dimethyl fumarate (DMF) demonstrated a protective effect against OA in ERK1 knockout mice.
Conclusions:
- ERK1 plays a crucial role in regulating chondrocyte function and protecting against osteoarthritis progression.
- The protective effects of ERK1 involve maintaining Nrf2 nuclear transport and mitigating chondrocyte aging.
- Dimethyl fumarate (DMF), as an Nrf2 activator, shows promise as a therapeutic agent for osteoarthritis treatment.
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