{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:01:43Z","timestamp":1793142103563,"version":"4.5.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by abnormal bone metabolism, with few effective treatments available. Danshensu [3-(3,4-dihydroxy-phenyl) lactic acid) is a bioactive compound from traditional Chinese medicine with a variety of pharmacologic effects. In the present study, we investigated the pharmacologic effect and molecular mechanism of Danshensu in AS. Potential targets of Danshensu were identified in four drugs-genes databases; and potential pharmacologic target genes in AS were identified in three diseases-genes databases. Differentially expressed genes related to AS were obtained from the Gene Expression Omnibus database. Overlapping targets of Danshensu and AS were determined and a disease\u2013active ingredient\u2013target interaction network was constructed with Cytoscape software. Enrichment analyses of the common targets were performed using Bioconductor. To test the validity of the constructed network, an <jats:italic>in vitro<\/jats:italic> model was established by treating osteoblasts from newborn rats with low concentrations of tumor necrosis factor (TNF)-\u03b1. Then, the <jats:italic>in vitro<\/jats:italic> model and AS fibroblasts were treated with Danshensu (1\u201310\u00a0\u03bcM). Osteogenesis was evaluated by alkaline phosphatase staining and activity assay, alizarin red staining, quantitative PCR, and western blotting. We identified 2944 AS-related genes and 406 Danshensu targets, including 47 that were common to both datasets. The main signaling pathways associated with the targets were the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. A low concentration of TNF-\u03b1 (0.01\u00a0ng\/ml) promoted the differentiation of osteoblasts; this was inhibited by Danshensu, which had the same effect on AS fibroblasts but had the opposite effect on normal osteoblasts. Danshensu also decreased the phosphorylation of JNK and ERK in AS fibroblasts. There results provide evidence that Danshensu exerts an anti-osteogenic effect <jats:italic>via<\/jats:italic> suppression of JNK and ERK signaling, highlighting its therapeutic potential for the treatment of AS.<\/jats:p>","DOI":"10.3389\/fphar.2021.772190","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:56:58Z","timestamp":1638323818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Anti-Osteogenic Effect of Danshensu in Ankylosing Spondylitis: An in Vitro Study Based on Integrated Network Pharmacology"],"prefix":"10.3389","volume":"12","author":[{"given":"Jiaxiao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbo","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junying","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoling","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinrong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liao","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1080\/09205063.2018.1448336","article-title":"Chitosan Oligosaccharide Promotes Osteoclast Formation by Stimulating the Activation of MAPK and AKT Signaling Pathways","volume":"29","author":"Bai","year":"2018","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"B2","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1007\/s00441-015-2277-6","article-title":"Connexin 43 Promotes Ossification of the Posterior Longitudinal Ligament through Activation of the ERK1\/2 and P38 MAPK Pathways","volume":"363","author":"Chen","year":"2016","journal-title":"Cell Tissue Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3109\/17453679709003987","article-title":"Inflammatory Cytokines Regulate Proliferation of Cultured Human Osteoblasts","volume":"68","author":"Frost","year":"1997","journal-title":"Acta Orthop. Scand."},{"key":"B4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s13040-020-00229-4","article-title":"Exploring Active Ingredients and Function Mechanisms of Ephedra-Bitter almond for Prevention and Treatment of Corona Virus Disease 2019 (COVID-19) Based on Network Pharmacology","volume":"13","author":"Gao","year":"2020","journal-title":"BioData Min"},{"key":"B5","doi-asserted-by":"publisher","first-page":"36399","DOI":"10.18632\/oncotarget.16821","article-title":"The Role of Non-thermal Atmospheric Pressure Biocompatible Plasma in the Differentiation of Osteoblastic Precursor Cells, MC3T3-E1","volume":"8","author":"Han","year":"2017","journal-title":"Oncotarget"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.3390\/cells9112466","article-title":"Activation of C-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis","volume":"9","author":"Lai","year":"2020","journal-title":"Cells"},{"key":"B7","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1016\/j.bcp.2009.10.019","article-title":"The PI3K\/Akt\/FOXO3a\/p27Kip1 Signaling Contributes to Anti-inflammatory Drug-Suppressed Proliferation of Human Osteoblasts","volume":"79","author":"Li","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.biopha.2016.09.091","article-title":"Annexin A2, Up-Regulated by IL-6, Promotes the Ossification of Ligament Fibroblasts from Ankylosing Spondylitis Patients","volume":"84","author":"Li","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1002\/art.40468","article-title":"Inflammation Intensity-dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis","volume":"70","author":"Li","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"112764","DOI":"10.1016\/j.jep.2020.112764","article-title":"Integrated Network Pharmacology and Zebrafish Model to Investigate Dual-Effects Components of Cistanche Tubulosa for Treating Both Osteoporosis and Alzheimer's Disease","volume":"254","author":"Li","year":"2020","journal-title":"J. Ethnopharmacol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6090","DOI":"10.1002\/jcp.30313","article-title":"Osteoimmunological Insights into the Pathogenesis of Ankylosing Spondylitis","volume":"236","author":"Liu","year":"2021","journal-title":"J. Cel Physiol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.berh.2018.12.001","article-title":"Advances in Understanding the Pathophysiology of Spondyloarthritis","volume":"32","author":"Lories","year":"2018","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11926-017-0644-x","article-title":"The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management","volume":"19","author":"Magrey","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"B14","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1002\/art.24132","article-title":"Inflammatory Lesions of the Spine on Magnetic Resonance Imaging Predict the Development of New Syndesmophytes in Ankylosing Spondylitis: Evidence of a Relationship between Inflammation and New Bone Formation","volume":"60","author":"Maksymowych","year":"2009","journal-title":"Arthritis Rheum."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e22405","DOI":"10.1002\/jbt.22405","article-title":"Bilobalide Alleviates IL-17-induced Inflammatory Injury in ATDC5 Cells by Downregulation of microRNA-125a","volume":"33","author":"Mao","year":"2019","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"258","DOI":"10.3892\/ijmm.2015.2419","article-title":"Danshensu Protects against Ischemia\/reperfusion Injury and Inhibits the Apoptosis of H9c2 Cells by Reducing the Calcium Overload through the P-JNK-NF-\u039ab-TRPC6 Pathway","volume":"37","author":"Meng","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3789","DOI":"10.1002\/art.30627","article-title":"Radiographic Progression Is Associated with Resolution of Systemic Inflammation in Patients with Axial Spondylarthritis Treated with Tumor Necrosis Factor \u03b1 Inhibitors: a Study of Radiographic Progression, Inflammation on Magnetic Resonance Imaging, and Circulating Biomarkers of Inflammation, Angiogenesis, and Cartilage and Bone Turnover","volume":"63","author":"Pedersen","year":"2011","journal-title":"Arthritis Rheum."},{"key":"B18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s11926-017-0681-5","article-title":"Mechanism of New Bone Formation in Axial Spondyloarthritis","volume":"19","author":"Poddubnyy","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s11926-020-00924-5","article-title":"Treatment of Axial Spondyloarthritis: What Does the Future Hold","volume":"22","author":"Poddubnyy","year":"2020","journal-title":"Curr. Rheumatol. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1002\/jcb.26275","article-title":"Effect of Metformin on Ossification and Inflammation of Fibroblasts in Ankylosing Spondylitis: An In Vitro Study","volume":"119","author":"Qin","year":"2018","journal-title":"J. Cel Biochem"},{"key":"B21","doi-asserted-by":"publisher","first-page":"9087","DOI":"10.1007\/s11033-020-05910-9","article-title":"JAK\/STAT Pathway and Molecular Mechanism in Bone Remodeling","volume":"47","author":"Sanpaolo","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nrrheum.2017.188","article-title":"Enthesitis: from Pathophysiology to Treatment","volume":"13","author":"Schett","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1038\/s41467-018-04679-7","article-title":"Osteocytic Oxygen Sensing Controls Bone Mass through Epigenetic Regulation of Sclerostin","volume":"9","author":"Stegen","year":"2018","journal-title":"Nat. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s00223-017-0356-2","article-title":"Bone Disease in Axial Spondyloarthritis","volume":"102","author":"Van Mechelen","year":"2018","journal-title":"Calcif Tissue Int."},{"key":"B25","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1002\/art.40770","article-title":"Interleukin-17A Inhibition Diminishes Inflammation and New Bone Formation in Experimental Spondyloarthritis","volume":"71","author":"van Tok","year":"2019","journal-title":"Arthritis Rheumatol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2279","DOI":"10.21037\/apm-20-277","article-title":"Drug Treatment of Ankylosing Spondylitis and Related Complications: an Overlook Review","volume":"9","author":"Wang","year":"2020","journal-title":"Ann. Palliat. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"BSR20191805","DOI":"10.1042\/bsr20191805","article-title":"Silencing of SPARC Represses Heterotopic Ossification via Inhibition of the MAPK Signaling Pathway","volume":"39","author":"Wang","year":"2019","journal-title":"Biosci. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41401-021-00714-4","article-title":"Danshensu Alleviates Pseudo-typed SARS-CoV-2 Induced Mouse Acute Lung Inflammation","author":"Wang","year":"2021","journal-title":"Acta Pharmacol. Sin"},{"key":"B29","doi-asserted-by":"publisher","first-page":"118","DOI":"10.3892\/etm.2020.9550","article-title":"A Novel Danshensu\/tetramethypyrazine Derivative Attenuates Oxidative Stress-Induced Autophagy Injury via the AMPK-mTOR-Ulk1 Signaling Pathway in Cardiomyocytes","volume":"21","author":"Xie","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.biocel.2014.03.005","article-title":"Salvianolic Acid B Promotes Osteogenesis of Human Mesenchymal Stem Cells through Activating ERK Signaling Pathway","volume":"51","author":"Xu","year":"2014","journal-title":"Int. J. Biochem. Cel Biol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"07","DOI":"10.3389\/fphar.2017.00007","article-title":"The New Synthetic H2S-Releasing SDSS Protects MC3T3-E1 Osteoblasts against H2O2-Induced Apoptosis by Suppressing Oxidative Stress, Inhibiting MAPKs, and Activating the PI3K\/Akt Pathway","volume":"8","author":"Yan","year":"2017","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s13075-020-02208-w","article-title":"Efficacy and Safety of IL-17 Inhibitors for the Treatment of Ankylosing Spondylitis: a Systematic Review and Meta-Analysis","volume":"22","author":"Yin","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"B33","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3390\/molecules22050771","article-title":"Comparative Analysis of the Major Chemical Constituents in Salvia Miltiorrhiza Roots, Stems, Leaves and Flowers during Different Growth Periods by UPLC-TQ-MS\/MS and HPLC-ELSD Methods","volume":"22","author":"Zeng","year":"2017","journal-title":"Molecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"172710","DOI":"10.1016\/j.ejphar.2019.172710","article-title":"Therapeutic Potentials and Mechanisms of the Chinese Traditional Medicine Danshensu","volume":"864","author":"Zhang","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1111\/jcmm.16262","article-title":"Up-regulation of T\u03b2RIII Facilitates the Osteogenesis of Supraspinous Ligament-Derived Fibroblasts from Patients with Ankylosing Spondylitis","volume":"25","author":"Zhang","year":"2021","journal-title":"J. Cel Mol Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1559325819901239","DOI":"10.1177\/1559325819901239","article-title":"miR-21 May Act as a Potential Mediator between Inflammation and Abnormal Bone Formation in Ankylosing Spondylitis Based on TNF-\u03b1 Concentration-dependent Manner through the JAK2\/STAT3 Pathway","volume":"18","author":"Zou","year":"2020","journal-title":"Dose Response"},{"key":"B37","doi-asserted-by":"publisher","first-page":"933","DOI":"10.2147\/dddt.S97463","article-title":"Celastrol Inhibits Prostaglandin E2-Induced Proliferation and Osteogenic Differentiation of Fibroblasts Isolated from Ankylosing Spondylitis Hip Tissues In Vitro","volume":"10","author":"Zou","year":"2016","journal-title":"Drug Des. Devel Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.772190\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T01:57:03Z","timestamp":1638323823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.772190\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":37,"alternative-id":["10.3389\/fphar.2021.772190"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.772190","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,25]]},"article-number":"772190"}}