{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T10:22:03Z","timestamp":1783938123180,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> The lack of effective biomarkers makes it difficult to achieve early diagnosis and intervention for osteonecrosis of the femoral head (ONFH). Hence, we aimed to identify novel long noncoding RNA (lncRNA) biomarkers for ONFH.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> High-throughput RNA sequencing was performed to detect lncRNA and mRNA expression levels in subchondral bone samples from three patients with ONFH and three patients with femoral neck fractures. Integrated bioinformatics analyses were conducted to identify lncRNAs associated with ONFH development and their potential functions and signaling pathways. A co-expression network was constructed based on the gene time-series expression data in GSE113253. After selecting lncRNA GAS5 as a novel biomarker for ONFH, bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation assays were performed to verify the association between lncRNA GAS5 and osteogenic differentiation. Alkaline phosphatase (ALP) staining and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to measure the osteogenic phenotype and lncRNA GAS5 expression. Finally, for further validation, ONFH rat models were established, and lncRNA GAS5 expression in subchondral bone was detected by RT-qPCR.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We identified 126 and 959 differentially expressed lncRNAs and genes, respectively. lncRNA GAS5 expression level was significantly downregulated in patients with ONFH compared to the control group patients. The BMSC osteogenic differentiation assays showed that ALP activity increased gradually from days 3 to 7, while the lncRNA GAS5 expression level was significantly upregulated in the osteogenic differentiation induction groups. Furthermore, <jats:italic>in vivo<\/jats:italic> experiments suggested that the bone volume\/tissue volume value and trabecular thickness significantly decreased in the ONFH rat model group compared to the control group, whereas the trabecular space significantly increased in the ONFH group compared to the control group. In addition, the lncRNA GAS5 expression level significantly decreased in the ONFH rat model group.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The lncRNA GAS5 expression level was highly associated with BMSC osteogenic differentiation and was significantly downregulated in both the subchondral trabecular bone tissue of ONFH patients and ONFH rat models. Therefore, lncRNA GAS5 can serve as an ONFH osteogenic biomarker to provide an effective target for early diagnosis and molecular therapy of ONFH.<\/jats:p>","DOI":"10.3389\/fcell.2022.857612","type":"journal-article","created":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:35:15Z","timestamp":1648416915000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Osteogenesis-Related Long Noncoding RNA GAS5 as a Novel Biomarker for Osteonecrosis of Femoral Head"],"prefix":"10.3389","volume":"10","author":[{"given":"Guanzhi","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutian","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruomu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanshuai","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunzheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3238\/arztebl.2016.0031","article-title":"Atraumatic Femoral Head Necrosis in Adults","volume":"4","author":"Arbab","year":"2016","journal-title":"Dtsch Arztebl Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1016\/j.arth.2020.04.092","article-title":"Diagnosis of Osteonecrosis of the Femoral Head: Too Little, Too Late, and Independent of Etiology","volume":"35","author":"Boontanapibul","year":"2020","journal-title":"The J. Arthroplasty"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/biomedicines8030065","article-title":"Identification of Aberrantly-Expressed Long Non-coding Rnas in Osteoblastic Cells from Osteoporotic Patients","volume":"8","author":"Centofanti","year":"2020","journal-title":"Biomedicines"},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.3892\/etm.2019.8185","article-title":"LncRNA AWPPH Participates in the Development of Non-traumatic Osteonecrosis of Femoral Head by Upregulating Runx2","author":"Chen","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.ocl.2018.10.001","article-title":"Osteonecrosis of the Femoral Head","volume":"50","author":"Cohen-Rosenblum","year":"2019","journal-title":"Orthop. Clin. North America"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1007\/s11999-008-0220-9","article-title":"Surgical and Molecular Advances in Osteonecrosis: Editorial Comment","volume":"466","author":"Cui","year":"2008","journal-title":"Clin. Orthop. Relat. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.biopha.2018.11.103","article-title":"Dexamethasone Induces Osteoblast Apoptosis through ROS-PI3K\/AKT\/GSK3\u03b2 Signaling Pathway","volume":"110","author":"Deng","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B8","doi-asserted-by":"publisher","first-page":"7757","DOI":"10.26355\/eurrev_201909_18985","article-title":"LncRNA GAS5 Overexpression Alleviates the Development of Osteoporosis through Promoting Osteogenic Differentiation of MSCs via Targeting microRNA-498 to Regulate RUNX2","volume":"23","author":"Feng","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13287-020-02075-x","article-title":"LncRNA NORAD Promotes Bone Marrow Stem Cell Differentiation and Proliferation by Targeting miR-26a-5p in Steroid-Induced Osteonecrosis of the Femoral Head","volume":"12","author":"Fu","year":"2021","journal-title":"Stem Cel Res Ther"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1007\/s00264-018-4011-y","article-title":"Early Diagnosis and Treatment of Steroid-Induced Osteonecrosis of the Femoral Head","volume":"43","author":"Fu","year":"2019","journal-title":"Int. Orthopaedics (Sicot)"},{"key":"B11","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1186\/s13287-019-1498-0","article-title":"The Shift in the Balance between Osteoblastogenesis and Adipogenesis of Mesenchymal Stem Cells Mediated by Glucocorticoid Receptor","volume":"10","author":"Han","year":"2019","journal-title":"Stem Cel Res Ther"},{"key":"B12","doi-asserted-by":"publisher","first-page":"278","DOI":"10.3109\/14397595.2014.932038","article-title":"Epidemiology of Nontraumatic Osteonecrosis of the Femoral Head in Japan","volume":"25","author":"Ikeuchi","year":"2015","journal-title":"Mod. Rheumatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"105363","DOI":"10.1016\/j.jsbmb.2019.04.012","article-title":"IGF-1 Reverses the Osteogenic Inhibitory Effect of Dexamethasone on BMP9-Induced Osteogenic Differentiation in Mouse Embryonic FIbroblasts via PI3K\/AKT\/COX-2 Pathwayfibroblasts via PI3K\/AKT\/COX-2 Pathway","volume":"191","author":"Jiang","year":"2019","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1089\/dna.2020.5894","article-title":"Circular RNA and Messenger RNA Expression Profile and Competing Endogenous RNA Network in Subchondral Bone in Osteonecrosis of the Femoral Head","volume":"40","author":"Jiao","year":"2021","journal-title":"DNA Cel Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"9864","DOI":"10.1002\/jcp.29799","article-title":"Desferoxamine Protects against Glucocorticoid\u2010induced Osteonecrosis of the Femoral Head via Activating HIF\u20101\u03b1 Expression","volume":"235","author":"Jing","year":"2020","journal-title":"J. Cel Physiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"108912","DOI":"10.1016\/j.biopha.2019.108912","article-title":"Mesenchymal Stem Cell-Associated lncRNA in Osteogenic Differentiation","volume":"115","author":"Ju","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"B17","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2106\/JBJS.F.01582","article-title":"Fate of Untreated Asymptomatic Osteonecrosis of the Femoral Head","volume":"90","author":"Kwang","year":"2008","journal-title":"J. Bone Jt. Surg. - Ser. A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.bone.2019.03.008","article-title":"Discovery and Validation an Eight-Biomarker Serum Gene Signature for the Diagnosis of Steroid-Induced Osteonecrosis of the Femoral Head","volume":"122","author":"Li","year":"2019","journal-title":"Bone"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12405","article-title":"Emerging Roles of MicroRNAs in Osteonecrosis of the Femoral Head","volume":"51","author":"Li","year":"2018","journal-title":"Cell Prolif"},{"key":"B20","doi-asserted-by":"publisher","first-page":"8129","DOI":"10.1002\/jcp.29467","article-title":"Identification of Potential miRNA Biomarkers for Traumatic Osteonecrosis of Femoral Head","volume":"235","author":"Liu","year":"2020","journal-title":"J Cell Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.2106\/jbjs.19.01271","article-title":"Nontraumatic Osteonecrosis of the Femoral Head: Where Do We Stand Today?","volume":"102","author":"Mont","year":"2020","journal-title":"J. Bone Jt. Surg Am"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2689-4","article-title":"LncRNA ENST00000563492 Promoting the Osteogenesis-Angiogenesis Coupling Process in Bone Mesenchymal Stem Cells (BMSCs) by Functions as a ceRNA for miR-205-5p","volume":"11","author":"Ouyang","year":"2020","journal-title":"Cell Death Dis"},{"key":"B23","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/s41598-017-00162-3","article-title":"Region Specific Raman Spectroscopy Analysis of the Femoral Head Reveals that Trabecular Bone Is Unlikely to Contribute to Non-traumatic Osteonecrosis","volume":"7","author":"Pascart","year":"2017","journal-title":"Sci. Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1038\/s41374-021-00598-2","article-title":"LncRNA GAS5 Activates the HIF1A\/VEGF Pathway by Binding to TAF15 to Promote Wound Healing in Diabetic Foot Ulcers","volume":"101","author":"Peng","year":"2021","journal-title":"Lab. Invest."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1177\/0300060514554724","article-title":"Biomarkers and Pharmaceutical Strategies in Steroid-Induced Osteonecrosis of the Femoral Head: A Literature Review","volume":"43","author":"Qi","year":"2015","journal-title":"J. Int. Med. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1038\/s41588-019-0359-1","article-title":"Osteogenesis Depends on Commissioning of a Network of Stem Cell Transcription Factors that Act as Repressors of Adipogenesis","volume":"51","author":"Rauch","year":"2019","journal-title":"Nat. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2009","journal-title":"Bioinformatics"},{"key":"B28","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.jbspin.2011.04.013","article-title":"Interleukin-33: A Novel Player in Osteonecrosis of the Femoral Head?","volume":"78","author":"Saidi","year":"2011","journal-title":"Jt. Bone Spine"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1007\/s11010-020-04047-4","article-title":"lncRNA-CRNDE Regulates BMSC Chondrogenic Differentiation and Promotes Cartilage Repair in Osteoarthritis through SIRT1\/SOX9","volume":"476","author":"Shi","year":"2021","journal-title":"Mol. Cel Biochem"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1007\/s00264-018-4018-4","article-title":"Classification Systems of Hip Osteonecrosis: an Updated Review","volume":"43","author":"Sultan","year":"2019","journal-title":"Int. Orthopaedics (Sicot)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1007\/s00223-008-9111-z","article-title":"Influence of Factors Regulating Bone Formation and Remodeling on Bone Quality in Osteonecrosis of the Femoral Head","volume":"82","author":"Tingart","year":"2008","journal-title":"Calcif Tissue Int."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2021.729909","article-title":"Induction of PI3K\/Akt-Mediated Apoptosis in Osteoclasts Is a Key Approach for Buxue Tongluo Pills to Treat Osteonecrosis of the Femoral Head","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s12943-019-1013-3","article-title":"Novel lncRNA-IUR Suppresses Bcr-Abl-Induced Tumorigenesis through Regulation of STAT5-CD71 Pathway","volume":"18","author":"Wang","year":"2019","journal-title":"Mol. Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"110534","DOI":"10.1016\/j.mce.2019.110534","article-title":"Long Non-coding RNA GAS5 Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells by Regulating the miR-135a-5p\/FOXO1 Pathway","volume":"496","author":"Wang","year":"2019","journal-title":"Mol. Cell Endocrinol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms20225786","article-title":"S100 Calcium Binding Protein A9 Represses Angiogenic Activity and Aggravates Osteonecrosis of the Femoral Head","volume":"20","author":"Wu","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2021.12350","article-title":"lncRNA GAS5 Regulates Angiogenesis by Targeting miR-10a-3p\/VEGFA in Osteoporosis","volume":"24","author":"Wu","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1016\/j.arth.2019.09.001","article-title":"Platelet-Rich Plasma-Incorporated Autologous Granular Bone Grafts Improve Outcomes of Post-Traumatic Osteonecrosis of the Femoral Head","volume":"35","author":"Xian","year":"2020","journal-title":"J. Arthroplasty"},{"key":"B38","doi-asserted-by":"publisher","first-page":"18435","DOI":"10.1002\/jcb.29161","article-title":"The Role of lncRNA RP11\u2010154D6 in Steroid\u2010induced Osteonecrosis of the Femoral Head through BMSC Regulation","volume":"120","author":"Xiang","year":"2019","journal-title":"J. Cel Biochem"},{"key":"B39","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.omtn.2019.12.001","article-title":"m6A Methylation of Precursor-miR-320\/runx2 Controls Osteogenic Potential of Bone Marrow-Derived Mesenchymal Stem Cells","volume":"19","author":"Yan","year":"2020","journal-title":"Mol. Ther. - Nucleic Acids"},{"key":"B40","doi-asserted-by":"publisher","first-page":"8777","DOI":"10.18632\/aging.102264","article-title":"LncRNA MALAT1 Shuttled by Bone Marrow-Derived Mesenchymal Stem Cells-Secreted Exosomes Alleviates Osteoporosis through Mediating microRNA-34c\/SATB2 axis","volume":"11","author":"Yang","year":"2019","journal-title":"Aging"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40659-020-00309-z","article-title":"The Roles of miRNA, lncRNA and circRNA in the Development of Osteoporosis","volume":"53","author":"Yang","year":"2020","journal-title":"Biol. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.bone.2010.10.006","article-title":"Hypoxia-inducible Factor-1 Is a Positive Regulator of Sox9 Activity in Femoral Head Osteonecrosis","volume":"48","author":"Zhang","year":"2011","journal-title":"Bone"},{"key":"B43","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/jcsm.12281","article-title":"A Newly Identified lncRNA MAR1 Acts as a miR-487b Sponge to Promote Skeletal Muscle Differentiation and Regeneration","volume":"9","author":"Zhang","year":"2018","journal-title":"J. Cachexia, Sarcopenia Muscle"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1016\/j.bbrc.2018.06.146","article-title":"LncRNA EPIC1 Protects Human Osteoblasts from Dexamethasone-Induced Cell Death","volume":"503","author":"Zhangyang","year":"2018","journal-title":"Biochem. Biophysical Res. Commun."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.857612\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,27]],"date-time":"2022-03-27T21:35:23Z","timestamp":1648416923000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.857612\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,22]]},"references-count":44,"alternative-id":["10.3389\/fcell.2022.857612"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.857612","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,22]]},"article-number":"857612"}}