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Exp. Mol. Med., 03 February 2025 | https://doi.org/10.1038/s12276-025-01400-9 Increased oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in mice with surgically induced osteoarthritis

Jin Han^{1 2}, Yoon Hee Kim ¹, Seungwoo Han ^{3 4 5 *}

¹Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
²Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
³Laboratory for Arthritis and Cartilage Biology, Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
⁴Cell & Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
⁵Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

^*Corresponding author: correspondence to Seungwoo Han

Abstract

Chondrocytes can shift their metabolism to oxidative phosphorylation (OxPhos) in the early stages of osteoarthritis (OA), but as the disease progresses, this metabolic adaptation becomes limited and eventually fails, leading to mitochondrial dysfunction and oxidative stress. Here we investigated whether enhancing OxPhos through the inhibition of pyruvate dehydrogenase kinase (PDK) 2 affects the metabolic flexibility of chondrocytes and cartilage degeneration in a surgical model of OA. Among the PDK isoforms, PDK2 expression was increased by IL-1β in vitro and in the articular cartilage of the DMM model in vivo, accompanied by an increase in phosphorylated PDH. Mice lacking PDK2 showed significant resistance to cartilage damage and reduced pain behaviors in the DMM model. PDK2 deficiency partially restored OxPhos in IL-1β-treated chondrocytes, leading to increases in APT and the NAD⁺/NADH ratio. These metabolic changes were accompanied by a decrease in reactive oxygen species and senescence in chondrocytes, as well as an increase in the expression of antioxidant proteins such as NRF2 and HO-1 after IL-1β treatment. At the signaling level, PDK2 deficiency reduced p38 signaling and maintained AMPK activation without affecting the JNK, mTOR, AKT and NF-κB pathways. p38 MAPK signaling was critically involved in reactive oxygen species production under glycolysis-dominant conditions in chondrocytes. Our study provides a proof of concept for PDK2-mediated metabolic reprogramming toward OxPhos as a new therapeutic strategy for OA.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-03)
연구진국내 연구진
분야 생명과학 > 세포생물학

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