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Asiatic Acid Attenuates Bone Loss by Regulating Osteoclastic Differentiation

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Abstract

Anti-resorptive agents like bisphosphonates have been widely used for the treatment of postmenopausal osteoporosis. However, their long-term safety and efficacy are still controversial. This study is to examine the effect of Asiatic acid (AA) in osteoclastic differentiation, and further to investigate its effect on bone quality in animals. Effect of AA on osteoclastic differentiation was measured by Tartrate-resistant acid phosphatase stain, bone resorption pit assays, and quantitative real-time polymerase chain reaction. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor-β (TGF-β) signaling were measured by western blot before and after AA treatment. Ovariectomized (OVX) wild-type or Smad7 partially knock out mice were used to evaluate the effects of AA on bone quality by micro-computed tomography, mechanical test, and histomorphometry. Results revealed a dose-dependent inhibitory effect of AA on osteoclastic differentiation. After AA treatment, Smad7 was upregulated, while NF-κB and TGF-β signaling were inhibited during osteoclastic differentiation. Results from animal study revealed that AA prevented bone from further loss caused by OVX and increased the mechanical properties of femur in wild-type animals. AA also prevented bone loss in the Smad7-deficient animals. When combining with OVX in the Smad7-deficient mice, AA could only partially preserve their bone mass. Taken together, we found that AA effectively inhibited osteoclastic differentiation and attenuated osteoporosis, which effects may be through TGF-β and NF-κB pathways. This study reveals that AA may be a potential anti-resorptive agent for postmenopausal osteoporosis.

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Acknowledgements

This work was supported by grants from Hong Kong Government Research Grant Council, General Research Fund (14119115, 14120118, 14160917, 9054014 N_CityU102/15 and T13-402/17-N), Health and Medical Research Fund (16170951), the National Natural Science Foundation of China (81874000, 81430049, and 81772322), Natural Science Foundation of Guangdong Science and Technology Department (2018A030313374, 2016B030309002), Guangdong Medical Sciences and Technology Fund (A2018111), Guangdong Traditional Chinese Medicine Bureau Fund (20191184), and funds from Affiliated Hospital of Guangdong Medical University (526Z20170001, 21201DFK20190057). This study was also supported in part by SMART program, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong and the research was made possible by resources donated by Lui Che Woo Foundation Limited.

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Author notes

  1. Jianping Huang, Haixing Wang and Meiling Huang contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmacology, The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources, Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, People’s Republic of China

    Jianping Huang, Liao Cui & Sien Lin

  2. Department of Stomatology, Guangdong Medical University, Zhanjiang, People’s Republic of China

    Jianping Huang

  3. Department of Orthopaedics & Traumatology, Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People’s Republic of China

    Haixing Wang, Xiaoting Zhang, Yuk Wai Lee, Gang Li & Sien Lin

  4. The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People’s Republic of China

    Haixing Wang, Xiaoting Zhang, Yuk Wai Lee & Gang Li

  5. Department of Rehabilitation, The Second People’s Hospital of Shenzhen, Shenzhen, People’s Republic of China

    Meiling Huang

  6. Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, People’s Republic of China

    Zhixian Zong, Xinyou Wu, Jinchang Zheng, Bo Wei & Sien Lin

  7. Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China

    Jianbin Xu

  8. Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, People’s Republic of China

    Huiyao Lan

  9. The Chinese University of Hong Kong, Prince of Wales Hospital, Room 74038, 5/F, Lui Chee Woo Clinical Science Building, Shatin, NT, Hong Kong, SAR, People’s Republic of China

    Gang Li

  10. Minimally Invasive Orthopaedic Lab, 2/F, Clinical Skill Training Building, Affiliated Hospital of Guangdong Medical University, Xiashan, Zhanjiang, 524002, People’s Republic of China

    Sien Lin

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  1. Jianping Huang
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Correspondence to Gang Li or Sien Lin.

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Jianping Huang, Haixing Wang, Meiling Huang, Zhixian Zong, Xinyou Wu, Jianbin Xu, Huiyao Lan, Jinchang Zheng, Xiaoting Zhang, Yuk Wai Lee, Bo Wei, Liao Cui, Sien Lin, and Gang Li declare that they have no conflict of interest.

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All animal experiments were approved by the Animal Experimental Ethical Committee of the Chinese University of Hong Kong (Ref. No.: 15-081-MIS).

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Huang, J., Wang, H., Huang, M. et al. Asiatic Acid Attenuates Bone Loss by Regulating Osteoclastic Differentiation. Calcif Tissue Int 105, 531–545 (2019). https://doi.org/10.1007/s00223-019-00596-z

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