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      Baicalin Ameliorates Dexamethasone-Induced Osteoporosis by Regulation of the RANK/RANKL/OPG Signaling Pathway

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          Abstract

          Background

          Osteoporosis is a chronic bone metabolism disorder affecting millions of the world population. The RANKL/RANK/OPG signaling pathway has been confirmed to be the main regulator of osteoporosis. It is of great interest to identify appropriate therapeutic agents that can regulate the RANKL/RANK/OPG pathway. Baicalin (BA) is a well-known traditional Chinese medicine formula against various inflammatory diseases with a proven role of the RANKL/RANK/OPG pathway regulation. However, the potential effect of BA on osteoporosis and the mechanisms underlying this remain unclear. In the present study, we aimed to evaluate the efficacy of BA in the prevention of dexamethasone (DEX)-induced osteoporosis in zebrafish.

          Methods

          In this study, growth and development changes of zebrafish and calcein staining were assessed with a micrograph. The expression levels of RANKL and OPG and transcription factors in response to DEX induction and BA administration were evaluated by Western blotting and qRT-PCR. In addition, the intermolecular interactions of BA and RANKL were investigated by molecular docking.

          Results

          Results show that BA enhances the growth and development of dexamethasone (DEX)-induced osteoporosis in zebrafish larvae. Calcein staining and calcium and phosphorus determination revealed that BA ameliorates mineralization of DEX-induced osteoporosis zebrafish larvae. BA also regulates the expression of RANKL and OPG and hampers the changes in gene expression related to bone formation and resorption under the induction of DEX in zebrafish. It can be inferred by molecular docking that BA may interact directly with the extracellular domain of RANKL.

          Conclusion

          The findings, herein, reveal that BA ameliorates DEX-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway.

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          Most cited references 45

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          Functions of RANKL/RANK/OPG in bone modeling and remodeling.

          The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.
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            Leptin inhibits osteoclast generation.

            Originally, leptin was described as a product of adipocytes that acts on the hypothalamus to regulate appetite. However, subsequently, it has been shown that leptin receptors are distributed widely and that leptin has diverse functions, including promotion of hemopoietic and osteoblastic differentiation. It has been recognized for some time that both serum leptin and bone mass are correlated positively to body fat mass and, recently, we have shown a direct positive relationship between serum leptin and bone mass in nonobese women. We now report that leptin inhibits osteoclast generation in cultures of human peripheral blood mononuclear cells (PBMCs) and murine spleen cells incubated on bone in the presence of human macrophage colony-stimulating factor (hM-CSF) and human soluble receptor activator of NF-kappaB ligand (sRANKL). The half-maximal concentration inhibitory of leptin was approximately 20 nM in the presence of sRANKL at 40 ng/ml but decreased to approximately 2 nM when sRANKL was used at 5 ng/ml. The majority of the inhibitory effect occurred in the first week of the 3-week cultures. Inhibition did not occur when the PBMC cultures were washed vigorously to remove nonadherent cells or when purified CD14+ monocytes were used to generate osteoclasts, indicating an indirect or permissive effect via CD14- PBMC. Leptin increased osteoprotegerin (OPG) messenger RNA (mRNA) and protein expression in PBMC but not in CD14+ cells, suggesting that the inhibitory effect may be mediated by the RANKL/RANK/OPG system. Leptin may act locally to increase bone mass and may contribute to linkage of bone formation and resorption.
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              Tracking gene expression during zebrafish osteoblast differentiation.

              The transcription factors RUNX2 and OSX have been shown to act sequentially to direct mammalian osteoblast differentiation. RUNX2 is required during the early stages of commitment and acts in part to activate Osx transcription. OSX and RUNX2 then act to direct transcription of bone matrix proteins. Here, we investigate the expression of these genes and others during zebrafish osteoblastogenesis. Using whole-mount in situ hybridization, we find that, during the formation of a given bone, the zebrafish homologues of mouse Runx2 (runx2a and runx2b) are typically expressed before the onset of osx. osx expression is usually followed by up-regulation of the bone matrix proteins, col1a2 and osteonectin. These results suggest that the mammalian pathway is conserved during development of the head and shoulder skeleton of zebrafish. We also analyze the expression of three atypical bone markers (tcf7, cvl2, and col10a1) in an effort to place them within this canonical hierarchy.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                15 January 2020
                2020
                : 14
                : 195-206
                Affiliations
                [1 ]School of Pharmaceutical Sciences, Nanjing Tech University , Nanjing 211800, People’s Republic of China
                [2 ]Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture, Nanjing Tech University , Nanjing 211800, People’s Republic of China
                Author notes
                Correspondence: Ye Zhao; Chi-Meng Tzeng Email zhaoyev@163.com; tzengchimeng@njtech.edu.cn
                Article
                225516
                10.2147/DDDT.S225516
                6970258
                © 2020 Zhao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 1, References: 49, Pages: 12
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                rank, opg, rankl, baicalin, osteoporosis

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