{"title":"异硫氰酸紫光芪阻碍RANK/TRAF6相互作用抑制破骨细胞生成，促进体外成骨，减轻糖皮质激素诱导的大鼠骨质疏松症","authors":"Viney Kumar , Swati Haldar , Souvik Ghosh , Samrat Chauhan , Abhishek Sharma , Poonam Dhankhar , Amit Kumar , Satish Jaiswal , Saakshi Saini , Sumeet Gupta , Debrupa Lahiri , Partha Roy","doi":"10.1016/j.bcp.2022.115284","DOIUrl":null,"url":null,"abstract":"<div><p><span><span>Prolonged glucocorticoid<span> treatment often leads to glucocorticoid-induced osteoporosis (GIOP), a common iatrogenic complication. This study has explored the anti-osteoporotic potential of semi-synthetic compound, </span></span>pterostilbene<span> isothiocyanate (PTER-ITC) in GIOP rat model and bone formation potential </span></span><em>in vitro</em>. Dysregulated bone-remodelling leads to osteoporosis. PTER-ITC has shown anti-osteoclastogenic activity <em>in vitro</em>. However, its molecular target remains unidentified, which has been explored in this study through <em>in silico</em><span><span> and experimental approaches. Alizarin Red S and von-Kossa staining, and </span>alkaline phosphatase (ALP) activity showed the osteogenic differentiation potential of PTER-ITC in pre-osteoblastic mouse MC3T3-E1 and human hFOB 1.19 cells, further, confirmed through the expressions of osteogenic markers at transcriptional (RT-qPCR) and translational (immunoblotting) levels. The anti-osteoclastogenic property of PTER-ITC was confirmed through inhibition of actin ring formation in mouse RAW 264.7 and human THP-1 macrophagic cells. Molecular docking and molecular dynamic simulation showed that PTER-ITC inhibited the crucial osteoclastogenic RANK/TRAF6 interaction, which was further confirmed biochemically through co-immunoprecipitation assay. Osteoporotic bone architecture [validated through scanning electron microscopy (SEM), X-ray radiography, and micro-computed tomography (µ-CT)], physiology (confirmed through compression testing, Young’s modulus and stress </span><em>versus</em><span> strain output) and histology (verified through hematoxylin-eosin, Alizarin Red S, von-Kossa and Masson-trichrome staining) of PTER-ITC-treated GIOP female Wistar rats<span> were assuaged. Osteoporotic amelioration through PTER-ITC treatment was further substantiated through serum biomarkers, like, parathyroid hormone (PTH), ALP, calcium (Ca</span></span><sup>2+</sup><span>), Procollagen type I </span><em>N</em><span>-terminal propeptide (P1NP), and 25-hydroxy vitamin D. In conclusion, this study identifies the molecular target of PTER-ITC in impeding osteoclastogenesis and facilitating osteogenesis to ameliorate osteoporosis.</span></p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"206 ","pages":"Article 115284"},"PeriodicalIF":5.3000,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Pterostilbene-isothiocyanate impedes RANK/TRAF6 interaction to inhibit osteoclastogenesis, promoting osteogenesis in vitro and alleviating glucocorticoid induced osteoporosis in rats\",\"authors\":\"Viney Kumar , Swati Haldar , Souvik Ghosh , Samrat Chauhan , Abhishek Sharma , Poonam Dhankhar , Amit Kumar , Satish Jaiswal , Saakshi Saini , Sumeet Gupta , Debrupa Lahiri , Partha Roy\",\"doi\":\"10.1016/j.bcp.2022.115284\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span>Prolonged glucocorticoid<span> treatment often leads to glucocorticoid-induced osteoporosis (GIOP), a common iatrogenic complication. This study has explored the anti-osteoporotic potential of semi-synthetic compound, </span></span>pterostilbene<span> isothiocyanate (PTER-ITC) in GIOP rat model and bone formation potential </span></span><em>in vitro</em>. Dysregulated bone-remodelling leads to osteoporosis. PTER-ITC has shown anti-osteoclastogenic activity <em>in vitro</em>. However, its molecular target remains unidentified, which has been explored in this study through <em>in silico</em><span><span> and experimental approaches. Alizarin Red S and von-Kossa staining, and </span>alkaline phosphatase (ALP) activity showed the osteogenic differentiation potential of PTER-ITC in pre-osteoblastic mouse MC3T3-E1 and human hFOB 1.19 cells, further, confirmed through the expressions of osteogenic markers at transcriptional (RT-qPCR) and translational (immunoblotting) levels. The anti-osteoclastogenic property of PTER-ITC was confirmed through inhibition of actin ring formation in mouse RAW 264.7 and human THP-1 macrophagic cells. Molecular docking and molecular dynamic simulation showed that PTER-ITC inhibited the crucial osteoclastogenic RANK/TRAF6 interaction, which was further confirmed biochemically through co-immunoprecipitation assay. Osteoporotic bone architecture [validated through scanning electron microscopy (SEM), X-ray radiography, and micro-computed tomography (µ-CT)], physiology (confirmed through compression testing, Young’s modulus and stress </span><em>versus</em><span> strain output) and histology (verified through hematoxylin-eosin, Alizarin Red S, von-Kossa and Masson-trichrome staining) of PTER-ITC-treated GIOP female Wistar rats<span> were assuaged. Osteoporotic amelioration through PTER-ITC treatment was further substantiated through serum biomarkers, like, parathyroid hormone (PTH), ALP, calcium (Ca</span></span><sup>2+</sup><span>), Procollagen type I </span><em>N</em><span>-terminal propeptide (P1NP), and 25-hydroxy vitamin D. In conclusion, this study identifies the molecular target of PTER-ITC in impeding osteoclastogenesis and facilitating osteogenesis to ameliorate osteoporosis.</span></p></div>\",\"PeriodicalId\":8806,\"journal\":{\"name\":\"Biochemical pharmacology\",\"volume\":\"206 \",\"pages\":\"Article 115284\"},\"PeriodicalIF\":5.3000,\"publicationDate\":\"2022-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0006295222003781\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0006295222003781","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Pterostilbene-isothiocyanate impedes RANK/TRAF6 interaction to inhibit osteoclastogenesis, promoting osteogenesis in vitro and alleviating glucocorticoid induced osteoporosis in rats
Prolonged glucocorticoid treatment often leads to glucocorticoid-induced osteoporosis (GIOP), a common iatrogenic complication. This study has explored the anti-osteoporotic potential of semi-synthetic compound, pterostilbene isothiocyanate (PTER-ITC) in GIOP rat model and bone formation potential in vitro. Dysregulated bone-remodelling leads to osteoporosis. PTER-ITC has shown anti-osteoclastogenic activity in vitro. However, its molecular target remains unidentified, which has been explored in this study through in silico and experimental approaches. Alizarin Red S and von-Kossa staining, and alkaline phosphatase (ALP) activity showed the osteogenic differentiation potential of PTER-ITC in pre-osteoblastic mouse MC3T3-E1 and human hFOB 1.19 cells, further, confirmed through the expressions of osteogenic markers at transcriptional (RT-qPCR) and translational (immunoblotting) levels. The anti-osteoclastogenic property of PTER-ITC was confirmed through inhibition of actin ring formation in mouse RAW 264.7 and human THP-1 macrophagic cells. Molecular docking and molecular dynamic simulation showed that PTER-ITC inhibited the crucial osteoclastogenic RANK/TRAF6 interaction, which was further confirmed biochemically through co-immunoprecipitation assay. Osteoporotic bone architecture [validated through scanning electron microscopy (SEM), X-ray radiography, and micro-computed tomography (µ-CT)], physiology (confirmed through compression testing, Young’s modulus and stress versus strain output) and histology (verified through hematoxylin-eosin, Alizarin Red S, von-Kossa and Masson-trichrome staining) of PTER-ITC-treated GIOP female Wistar rats were assuaged. Osteoporotic amelioration through PTER-ITC treatment was further substantiated through serum biomarkers, like, parathyroid hormone (PTH), ALP, calcium (Ca2+), Procollagen type I N-terminal propeptide (P1NP), and 25-hydroxy vitamin D. In conclusion, this study identifies the molecular target of PTER-ITC in impeding osteoclastogenesis and facilitating osteogenesis to ameliorate osteoporosis.
期刊介绍：
Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics.
The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process.
All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review.
While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
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