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Salidroside accelerates fracture healing through cell-autonomous and non-autonomous effects on osteoblasts

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Abstract

Salidroside (SAL), a major active component of Rhodiola rosea L., exhibits diverse pharmacological effects. However, the direct roles of SAL in fracture healing remain largely unknown. Here, we demonstrate that SAL significantly promotes proliferation by altering the cell-cycle distribution of osteoblastic cells. SAL also greatly stimulates osteoblast differentiation and mineralization by inducing the expression of Runx2 and Osterix. In addition to its osteoblast-autonomous effects, SAL can activate the HIF-1α pathway coupling of angiogenesis and osteogenesis through cell-non-autonomous effects. Our in vitro results suggest that SAL significantly up-regulates HIF-1α expression at the mRNA and protein levels. Furthermore, the nuclear translocation and transcriptional activity of HIF-1α and the HIF-responsive gene VEGF increase following SAL treatment. Our mechanistic study revealed that the regulation of osteoblastic proliferation and HIF-1α expression partly involves MAPK/ERK and PI3K/Akt signaling. Our in vivo analysis also demonstrated that SAL can promote angiogenesis within the callus and accelerate fracture healing. Thus, SAL promotes skeletal regeneration in cell-autonomous and cell-non-autonomous ways and might be a potential therapy for accelerating fracture healing.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (nos. 81273520, 81572852, and 81502256), the Great Program of the Science Foundation of Tianjin (nos. 12JCZDJC26300 and 15JCYBJC28900) and the Great Program for Science and Technology in Logistics College of Chinese People’s Armed Police Forces (nos. WHZ201202, WHB201404, WHB201405 and WHB201406).

Author contributions

Y.W. and Z.M.H. designed the experiments. X.Q.G. and J.Y. analyzed the data and wrote the manuscript. L.Q., C.W. and Y.Q. performed the in vitro experiments. X.Q.G. and L.L. prepared the figures. Z.M.L. and D.W. performed the animal experiments. All of the authors reviewed the manuscript.

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    Authors and Affiliations

    1. Tianjin Key Laboratory for Prevention and Control of Occupational and Environmental Hazards, Tianjin, People’s Republic of China

      Xiao Qin Guo & Yue Wang

    2. Department of Pathogenic Biology and Immunology, Logistics College of Chinese People’s Armed Police Forces, Dongli District, Huizhi Ring Road, No. 1, Tianjin, 300309, People’s Republic of China

      Xiao Qin Guo, Lin Qi, Jing Yang, Yue Wang, Zong Min Li, Ye Qu & Dan Wang

    3. Department of Stomatology, Affiliated Hospital of Logistics College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China

      Chuan Wang & Ze Min Han

    4. Department of Pharmacology, Logistics College of Chinese People’s Armed Police Forces, Tianjin, People’s Republic of China

      Ling Li

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    1. Xiao Qin Guo
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    Correspondence to Yue Wang or Ze Min Han.

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    The authors declare no conflicts of interest.

    Ethics statement

    All animal procedures were approved by the Ethics Committee of Logistics College of Chinese People’s Armed Police Forces. The care, use and treatment of mice were in compliance with the guidelines of the Care and Use of Laboratory Animals.

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    Xiao Qin Guo, Lin Qi and Jing Yang contributed equally to this work.

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    Guo, X.Q., Qi, L., Yang, J. et al. Salidroside accelerates fracture healing through cell-autonomous and non-autonomous effects on osteoblasts. Cell Tissue Res 367, 197–211 (2017). https://doi.org/10.1007/s00441-016-2535-2

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    • DOI: https://doi.org/10.1007/s00441-016-2535-2

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