Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis

Moon Jong Chang,Seung-Baik Kang,Jeeyeon Lee,Donghyun Kang,Jisu Jung,Jin-Hong Kim,Bradley A Carlson,Chong Bum Chang,Byung Cheon Lee,Vadim N Gladyshev,Dolph L Hatfield,Byeong Jae Lee

doi:10.1038/s41467-022-28385-7

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.

Highlights

Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis
We demonstrate that selenophosphate synthetase 1 (SEPHS1) is an essential regulator of selenium metabolism, whose deficiency limits the synthesis of stress-related selenoproteins and disrupts redox homeostasis in chondrocytes
Since the stress-related selenoproteins downregulated by SEPHS1 deficiency have oxidoreductase functions, we examined the impact of Sephs[1] knockout on reactive oxygen species (ROS) levels in chondrocytes

Summary

Introduction

Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. Accumulating evidence indicates that imbalance in redox status resulting in oxidative stress in chondrocytes is a crucial event that disturbs cartilage homeostasis during OA development[5,6,7,8,9,10]. SEPHS2 forms a complex with SEPHS1 and Sec synthase (SEPSECS)[13,14], which in turn catalyzes the formation of Sec tRNA[Ser]Sec. There has been growing interest in the potential significance of the selenium metabolic pathway in the pathogenesis of OA, considering the role of selenoproteins in redox regulation[15] and the detrimental effects of oxidative stress in OA development[7,8,9,10]. We demonstrate that SEPHS1 is an essential regulator of selenium metabolism, whose deficiency limits the synthesis of stress-related selenoproteins and disrupts redox homeostasis in chondrocytes. The dysregulated selenium metabolic pathway triggers oxidative damage and induces chondrocyte senescence, thereby accelerating degenerative processes of the cartilage matrix during OA pathogenesis

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