Timosaponin AIII attenuates inflammatory injury in AGEs-induced osteoblast and alloxan-induced diabetic osteoporosis zebrafish by modulating the RAGE/MAPK signaling pathways

  • Phytomedicine. 2020 May 24;75:153247. doi: 10.1016/j.phymed.2020.153247.
Nani Wang  1 ,  Pingcui Xu  2 ,  Xuping Wang  2 ,  Weixuan Yao  3 ,  Binjie Wang  3 ,  Yuanzhao Wu  3 ,  Dan Shou  4
Affiliations
  • 1. Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China.. Electronic address: [email protected].
  • 2. Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China.
  • 3. The Department of Criminal Science and Technology, Zhejiang Police College, Hangzhou 310053, China.
  • 4. Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310007, China.. Electronic address: [email protected].
PMID: 32502823 DOI: 10.1016/j.phymed.2020.153247
Abstract

Background: Advanced glycation end products (AGEs) deposition causes inflammatory injury in osteoblasts and contributes to diabetic osteoporosis. The receptor for advanced glycation end product/mitogen-activated protein kinase pathway (RAGE/MAPK) signaling pathway is closely linked to the pathogenesis of diabetic osteoporosis. Timosaponin AIII, a steroidal saponin isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), shows anti-inflammatory and anti-osteoporosis effects.

Purpose: The present study was aimed to investigate the therapeutic effects of timosaponin AIII on diabetic osteoporosis and whether its effect is dependent on protecting osteoblasts against AGEs-induced injury via RAGE/MAPK signaling suppression.

Methods: An alloxan-induced diabetic osteoporosis zebrafish model was applied to investigate the effects of timosaponin AIII in vivo, and alendronate was used as a positive control. Moreover, related mechanisms were explored in primary rat osteoblasts. Molecular docking was applied to investigate the interactions between timosaponin AIII and RAGE.

Results: Timosaponin AIII treatment reversed alloxan-induced reduction in the mineralized area of the larvae head skeleton, accompanied by a decreased level of triglyceride and total Cholesterol in the zebrafish. Additionally, AGEs significantly influenced RAGE expression, Alkaline Phosphatase activity, interleukin 1β expression, interleukin 6 expression, and tumor necrosis factor-α expression, and increased cell Apoptosis. Timosaponin AIII significantly downregulated AGEs-induced interleukin 1β, interleukin 6, and tumor necrosis factor-α levels, and upregulated Alkaline Phosphatase and osteocalcin levels. Timosaponin AIII also significantly reduced the expression of RAGE and had additive effects on downstream P38, extracellular signal-regulated kinase and c-Jun N-terminal kinase in AGEs-induced osteoblast. Molecular docking predicted that hydrogen and hydrophobic interactions occurred between timosaponin AIII and RAGE.

Conclusion: These data clarified that timosaponin AIII attenuates diabetic osteoporosis via a novel mechanism involved suppressing the RAGE/MAPK signaling pathway. Our finding highlights the potential value of timosaponin AIII as an anti-diabetic osteoporosis agent.

Keywords
RAGE; Timosaponin AIII; diabetic osteoporosis; osteoblast.
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