Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis

Donghyun Kang, Jeeyeon Lee, Jisu Jung, Bradley A. Carlson, Moon Jong Chang, Chong Bum Chang, Seung-Baik Kang, Byung Cheon Lee, Vadim N. Gladyshev, Dolph L. Hatfield, Byeong Jae Lee () and Jin-Hong Kim ()
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Donghyun Kang: Institute for Basic Science
Jeeyeon Lee: Institute for Basic Science
Jisu Jung: Seoul National University
Bradley A. Carlson: National Institutes of Health
Moon Jong Chang: Seoul National University College of Medicine, Boramae Hospital
Chong Bum Chang: Seoul National University Bundang Hospital
Seung-Baik Kang: Seoul National University College of Medicine, Boramae Hospital
Byung Cheon Lee: Korea University
Vadim N. Gladyshev: Brigham and Women’s Hospital and Harvard Medical School
Dolph L. Hatfield: National Institutes of Health
Byeong Jae Lee: Seoul National University
Jin-Hong Kim: Institute for Basic Science

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.

Date: 2022
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DOI: 10.1038/s41467-022-28385-7

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