2. Academic Validation
  3. ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1

ED-71 Ameliorates Bone Loss in Type 2 Diabetes Mellitus by Enhancing Osteogenesis Through Upregulation of the Circadian Rhythm Coregulator BMAL1

  • Drug Des Devel Ther. 2024 Aug 29:18:3903-3919. doi: 10.2147/DDDT.S470684.
Ting Liu 1 2,  Luxu Wang 1 2 3,  Tuo Shi 4,  Hongrui Liu 1 2,  Bo Liu 5,  Jie Guo 1 2,  Minqi Li 1 2 5
Affiliations

Affiliations

  • 1 Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People's Republic of China.
  • 2 Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan, People's Republic of China.
  • 3 School of Stomatology, Jinzhou Medical University, Jinzhou, People's Republic of China.
  • 4 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People's Republic of China.
  • 5 School of Clinical Medicine, Jining Medical University, Jining, People's Republic of China.
PMID: 39224902 DOI: 10.2147/DDDT.S470684
Abstract

Purpose: Bone loss is a common complication of type 2 diabetes mellitus (T2DM). Circadian rhythms play a significant role in T2DM and bone remodeling. Eldecalcitol (ED-71), a novel active vitamin D analog, has shown promise in ameliorating T2DM. We aimed to investigate whether the circadian rhythm coregulator BMAL1 mediates the anti-osteoporotic effect of ED-71 in T2DM and its associated mechanisms.

Methods: A T2DM mouse model was established using high-fat diet (HDF) and streptozotocin (STZ) injection, and blood glucose levels were monitored weekly. HE staining, Masson staining, and Micro-CT were performed to assess the changes in bone mass. IHC staining and IF staining were used to detect osteoblast status and BMAL1 expression and RT-qPCR was applied to detect the change of oxidative stress factors. In vitro, high glucose (HG) stimulation was used to simulate the cell environment in T2DM. RT-qPCR, Western blot, IF, ALP staining and AR staining were used to detect osteogenic differentiation and SIRT1/GSK3β signaling pathway. DCFH-DA staining was used to detect Reactive Oxygen Species (ROS) levels.

Results: ED-71 increased bone mass and promoted osteogenesis in T2DM mice. Moreover, ED-71 inhibited oxidative stress and promoted BMAL1 expression in osteoblasts The addition of STL1267, an agonist of the BMAL1 transcriptional repressor protein REV-ERB, reversed the inhibitory effect of ED-71 on oxidative stress and the promotional effect on osteogenic differentiation. In addition, ED-71 facilitated SIRT1 expression and reduced GSK3β activity. The inhibition of SIRT1 with EX527 partially attenuated ED-71's effects, whereas the GSK3β inhibitor LiCl further enhanced ED-71's positive effects on BMAL1 expression.

Conclusion: ED-71 ameliorates bone loss in T2DM by upregulating the circadian rhythm coregulator BMAL1 and promoting osteogenesis through inhibition of oxidative stress. The SIRT1/GSK3β signaling pathway is involved in the regulation of BMAL1.

Keywords

BMAL1; SIRT1/GSK3β signaling pathway; eldecalcitol; osteoblast; type 2 diabetic mellitus.

Figures
Products