Tanshinol alleviates impaired bone formation by inhibiting adipogenesis via KLF15/PPARγ2 signaling in GIO rats

Authors: Ya-jun YANG1, Zhu ZHU2, Dong-tao WANG3, Xin-le ZHANG1, Yu-yu LIU1, Wen-xiu LAI1, Yu-lin MO1, Jin LI1, Yan-long LIANG1, Zhuo-qing HU1, Yong-jie YU1, Liao CUI1,4
1 Department of Pharmacology, Guangdong Medical University, Zhanjiang 524023, China
2 Sino-American Cancer Research Institute, Guangdong Medical University, Dongguan 523808, China
3 Department of Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen 518000, China
4 Guangdong Key Laboratory for R&D of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
Corresponding to: Ya-jun YANG:, Liao CUI:,
DOI: 10.1038/aps.2017.134
Received: 11 January 2018
Accepted: 12 June 2017
Advance online: 18 September 2017


Glucocorticoid (GC)-induced osteoporosis (GIO) is characterized by impaired bone formation, which can be alleviated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. In this study we investigated the molecular mechanisms underlying GC-induced modulation of osteogenesis as well as the possibility of using tanshinol to interfere with GIO. Female SD rats aged 4 months were orally administered distilled water (Con), prednisone (GC, 5 mg·kg-1·d-1), GC plus tanshinol (Tan, 16 mg·kg-1·d-1) or GC plus resveratrol (Res, 5 mg·kg-1·d-1) for 14 weeks. After the rats were sacrificed, samples of bone tissues were collected. The changes in bone formation were assessed using Micro-CT, histomorphometry, and biomechanical assays. Expression of Kruppel-like factor 15 (KLF15), peroxisome proliferator-activated receptor γ 2 (PPARγ 2) and other signaling proteins in skeletal tissue was measured with Western blotting and quantitative RT-PCR. GC treatment markedly increased the expression of KLF15, PPARγ2, C/EBPα and aP2, which were related to adipogenesis, upregulated FoxO3a pathway proteins (FoxO3a and Gadd45a), and suppressed the canonical Wnt signaling (β-catenin and Axin2), which was required for osteogenesis. Thus, GC significantly decreased bone mass and bone quality. Co-treatment with Tan or Res effectively counteracted GC-impaired bone formation, suppressed GC-induced adipogenesis, and restored abnormal expression of the signaling molecules in GIO rats. We conclude that tanshinol counteracts GC-decreased bone formation by inhibiting marrow adiposity via the KLF15/PPARγ2/FoxO3a/Wnt pathway.
Keywords: glucocorticoid-induced osteoporosis (GIO); tanshinol; resveratrol; bone formation; Kruppel-like factor 15 (KLF 15); PPARγ 2; adipogenesis