Drug Design, Development and Therapy (Nov 2022)
ED-71 Prevents Glucocorticoid-Induced Osteoporosis by Regulating Osteoblast Differentiation via Notch and Wnt/β-Catenin Pathways
Abstract
Xing Rong,1,2 Yuying Kou,1,2 Yuan Zhang,1,2 Panpan Yang,1,2 Rong Tang,1,2 Hongrui Liu,1,2 Minqi Li1,2 1Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, People’s Republic of China; 2Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Minqi Li; Hongrui Liu, Center of Osteoporosis and Bone Mineral Research, Shandong University, Department of Bone Metabolism, School of Stomatology, Shandong University, Wenhua West Road 44-1, Jinan, 250012, People’s Republic of China, Tel +86-531-88382095 ; +86-531-88382493, Fax +86-531-8838 2923, Email [email protected]; [email protected]: Long-term glucocorticoid- usage can lead to glucocorticoid-induced osteoporosis (GIOP). The study focused on the preventative effects of a novel active vitamin D3 analog, eldecalcitol (ED-71), against GIOP and explored the underlying molecular mechanisms.Methods: Intraperitoneal injection of methylprednisolone (MPED) or dexamethasone (DEX) induced the GIOP model within C57BL/6 mice in vivo. Simultaneously, ED-71 was orally supplemented. Bone histological alterations, microstructure parameters, novel bone formation rates, and osteogenic factor changes were evaluated by hematoxylin-eosin (HE) staining, micro-computed tomography, calcein/tetracycline labeling, and immunohistochemical (IHC) staining. The osteogenic differentiation level and mineralization in pre-osteoblast MC3T3-E1 cells were evaluated in vitro using alkaline phosphatase (ALP) staining, alizarin red (AR) staining, quantitative polymerase chain reaction (qPCR), Western blotting, and immunofluorescence staining.Results: ED-71 partially prevented bone mass reduction and microstructure parameter alterations among GIOP-induced mice. Moreover, ED-71 also promoted new bone formation and osteoblast activity while inhibiting osteoclasts. In vitro, ED-71 promoted osteogenic differentiation and mineralization in DEX-treated MC3T3-E1 cells and boosted the levels of osteogenic-related factors. Additionally, GSK3-β and β-catenin expression levels were elevated after ED-71 was added to cells and were accompanied by reduced Notch expression. The Wnt signaling inhibitor XAV939 and Notch overexpression reversed the ED-71 promotional effects toward osteogenic differentiation and mineralization.Conclusion: ED-71 prevented GIOP by enhancing osteogenic differentiation through Notch and Wnt/GSK-3β/β-catenin signaling. The results provide a novel translational direction for the clinical application of ED-71 against GIOP.Keywords: glucocorticoid-induced osteoporosis, eldecalcitol, osteoblasts, Notch signaling, Wnt/GSK-3β/β-catenin signaling
