Chlorogenic Acid Prevents Osteoporosis by Shp2/PI3K/Akt Pathway in Ovariectomized Rats

Cortex Eucommiae is used worldwide in traditional medicine, various constituents of Cortex Eucommiae, such as chlorogenic acid (CGA), has been reported to exert anti-osteoporosis activity in China, but the mechanism about their contribution to the overall activity is limited. The aims of this study...

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Bibliographic Details
Published in:	PloS one Vol. 11; no. 12; p. e0166751
Main Authors:	Zhou, Rong Ping, Lin, Si Jian, Wan, Wen Bing, Zuo, Hui Ling, Yao, Fen Fen, Ruan, Hui Bing, Xu, Jin, Song, Wei, Zhou, Yi Cheng, Wen, Shi Yao, Dai, Jiang Hua, Zhu, Mei Lan, Luo, Jun
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 29-12-2016 Public Library of Science (PLoS)
Subjects:	1-Phosphatidylinositol 3-kinase Acids AKT protein Alkaline phosphatase Animals Biocompatibility Biological activity Biology and Life Sciences Biomedical materials Bone Density - drug effects Bone mineral density Bone turnover Bones Cell Differentiation - drug effects Cell Proliferation - drug effects Cells, Cultured Chlorogenic acid Chlorogenic Acid - pharmacology Chromones - pharmacology Computed tomography Computer architecture Concentration (composition) Cyclin D1 Cyclin D1 - metabolism Differentiation Drugs Engineering research Enzyme inhibitors Estrogens Ethinylestradiol Eucommia ulmoides Female Femur Gene expression Glial stem cells Health aspects Hormone replacement therapy Humans Medicine and Health Sciences Mesenchymal Stromal Cells - cytology Mesenchyme Metabolism Morpholines - pharmacology Osteoblastogenesis Osteoblasts Osteoblasts - cytology Osteoblasts - metabolism Osteogenesis - drug effects Osteoporosis Osteoporosis, Postmenopausal - prevention & control Osteoprogenitor cells Ovariectomy Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - metabolism Physiological aspects Phytochemicals Post-menopause Prevention Protein kinases Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Sprague-Dawley Rehabilitation Ribonucleic acid RNA RNA Interference RNA, Small Interfering - genetics RNA-mediated interference Stem cells Subgroups Womens health China
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Summary:	Cortex Eucommiae is used worldwide in traditional medicine, various constituents of Cortex Eucommiae, such as chlorogenic acid (CGA), has been reported to exert anti-osteoporosis activity in China, but the mechanism about their contribution to the overall activity is limited. The aims of this study were to determine whether chlorogenic acid can prevent estrogen deficiency-induced osteoporosis and to analyze the mechanism of CGA bioactivity. The effect of CGA on estrogen deficiency-induced osteoporosis was performed in vivo. Sixty female Sprague-Dawley rats were divided randomly among a sham-operated group and five ovariectomy (OVX) plus treatment subgroups: saline vehicle, 17α-ethinylestradiol (E2), or CGA at 9, 27, or 45 mg/kg/d. The rats' femoral metaphyses were evaluated by micro-computed tomography (μCT). The mechanism of CGA bioactivity was investigated in vitro. Bone mesenchymal stem cells (BMSCs) were treated with CGA, with or without phosphoinositide 3-kinase (PI3K) inhibitor LY294002. BMSCs proliferation and osteoblast differentiation were assessed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and alkaline phosphatase, with or without Shp2 interfering RNA (RNAi). The results display that CGA at 27 and 45 mg/kg/day inhibited the decrease of bone mineral density (BMD) that induced by OVX in femur (p< 0.01), significantly promoted the levels of bone turnover markers, and prevented bone volume fraction (BV/TV), connectivity density (CoonD), trabecular number (Tb.N), trabecular thickness (Tb.Th) (all p< 0.01) to decrease and prevented the trabecular separation (Tb.Sp), structure model index (SMI)(both p< 0.01) to increase. CGA at 1 or 10 μM enhanced BMSC proliferation in a dose-dependent manner. CGA at 0.1 to 10 μM increased phosphorylated Akt (p-Akt) and cyclin D1. These effects were reversed by LY294002. CGA at 1 or 10 μM increased BMSC differentiation to osteoblasts (p< 0.01), Shp2 RNAi suppressed CGA-induced osteoblast differentiation by decreasing Shp2, p-Akt, and cyclin D1. This study found that CGA improved the BMD and trabecular micro-architecture for the OVX-induced osteoporosis. Therefore, CGA might be an effective alternative treatment for postmenopausal osteoporosis. CGA promoted proliferation of osteoblast precursors and osteoblastic differentiation of BMSCs via the Shp2/PI3K/Akt/cyclin D1 pathway.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Conceptualization: JL RPZ.Data curation: YCZ SYW.Formal analysis: FFY MLZ.Funding acquisition: JL RPZ.Investigation: JHD MLZ.Methodology: RPZ SJL WBW.Project administration: JL RPZ.Resources: JL RPZ.Software: HLZ JHD MLZ.Supervision: FFY.Validation: JL RPZ.Visualization: HBR.Writing – original draft: HBR JX WS.Writing – review & editing: RPZ WBW. Competing Interests: The authors have declared that no competing interests exist. These authors also contributed equally to this work.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0166751