Vitamin K2 Can Rescue the Dexamethasone-Induced Downregulation of Osteoblast Autophagy and Mitophagy Thereby Restoring Osteoblast Function In Vitro and In Vivo.

Liang Chen,Jia-Hao Tang,Zhong-Jie Xie,Xiang Shi,Jun Xie,De-Yi Yan,Bing-Zhang Wang,She-Ji Weng,Lei Yang,Zong-Yi Wu

doi:10.3389/fphar.2020.01209

Abstract

Chronic long-term glucocorticoids (GC) use is associated with glucocorticoid-induced osteoporosis (GIOP) by inhibiting the survival and impairing the functions of osteoblasts. Autophagy and mitophagy play key roles in osteoblast differentiation, mineralization and survival, and mounting evidence have implicated osteoblast autophagy and mitophagy as a novel mechanism in the pathogenesis of GIOP. Vitamin K2 (VK2) is an essential nutrient supplement that have been shown to exert protective effects against osteoporotic bone loss including GIOP. In this study, we showed that the glucocorticoid dexamethasone (Dex) deregulated osteoblast autophagy and mitophagy by downregulating the expression of autophagic and mitophagic markers LC3-II, PINK1, Parkin. This consequently led to inhibition of osteoblast differentiation and mineralization function in vitro. Interestingly, co-treatment with VK2 significantly attenuated the Dex-induced downregulation of LC3-II, PINK1, Parkin, thereby restoring autophagic and mitophagic processes and normal osteoblastic activity. In addition, using an established rat model of GIOP, we showed that VK2 administration can protect rats against the deleterious effects of Dex on bone by reinstating autophagic and mitophagic activities in bone tissues. Collectively, our results provide new insights into the role of osteoblast autophagy and mitophagy in GIOP. Additionally, the use of VK2 supplementation to augment osteoblast autophagy/mitophagy may significantly improve clinical outcomes of GIOP patients.

Highlights

Glucocorticoids (GC), are widely used clinically for the treatment of allergic and autoimmune diseases and cancer owing to their anti-inflammatory and immunosuppressive properties (Rizzoli and Biver, 2015)
We found that low concentrations of Dex treatment (1 and 5 mM) for 12 h upregulated the expression of autophagy and mitophagy related proteins LC3-II, PINK1 and Parkin (p
We further explored the inhibitory effect of Dex on autophagy by staining cells with MDC, a fluorescent marker that accumulates in autophagic vacuoles

Summary

Introduction

Glucocorticoids (GC), are widely used clinically for the treatment of allergic and autoimmune diseases and cancer owing to their anti-inflammatory and immunosuppressive properties (Rizzoli and Biver, 2015). Autophagy is a highly conserved homeostatic process that plays an essential part in the regulation of osteoblast differentiation and mineralization function (Liu et al, 2013; Nollet et al, 2014; Han et al, 2018; Lian et al, 2018) It has consistently been shown as a protective mechanism in maintaining osteoblast viability by allowing cells to survive various stresses (Todde et al, 2009; White and Lowe, 2009; Gu et al, 2016; Yang et al, 2016; Zhu et al, 2019; Zhao et al, 2020). Impaired mitophagic function have been reported to negatively impact osteoblast differentiation and mineralization function in vitro (Shen et al, 2018b; Jing et al, 2020) and the restoration of mitophagy helps alleviate steriod-induced bone loss in vivo (Zhang et al, 2020) Despite these encouraging reports, the precise role of autophagy and mitophagy in osteoblastic differentiation and function has not been thoroughly explored

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