{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T03:10:53Z","timestamp":1774321853495,"version":"3.50.1"},"reference-count":28,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteonecrosis of the femoral head (ONFH) induced by glucocorticoids (GCs) has been considered to be associated with the dysfunction of bone marrow mesenchymal stem cells (BMSCs). Studies have reported that GCs can regulate the normal differentiation of BMSCs. However, the exact mechanism of this regulation remains unclear. In this study, we used methylprednisolone (MPS) to induce BMSCs, and then found that the Hippo signaling pathway was upregulated in a dose-dependent manner compared to that in the control group. In addition, the osteogenic ability of BMSCs was decreased, as evaluated by Alizarin Red S staining analysis and alkaline phosphatase activity assays, accompanied by the downregulated expression of Runx2, osteopontin, and osteocalcin. Additionally, the adipogenic capacity of BMSCs under the MPS conditions was increased, as identified by Oil Red O staining with upregulated triglyceride and PPAR\u03b3 expression. Moreover, suppression by knockdown of MST1 was found to attenuate the Hippo signaling pathway and adipogenic differentiation, while enhancing osteogenic differentiation. In conclusion, our findings revealed that the Hippo signaling pathway was involved in GC-ONFH by affecting the osteogenic and adipogenic differentiation capacities of BMSCs. Our study could provide a basis for further investigation of the specific function of the Hippo pathway in ONFH.<\/jats:p>","DOI":"10.1515\/biol-2021-0102","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T23:18:35Z","timestamp":1635290315000},"page":"1130-1140","source":"Crossref","is-referenced-by-count":7,"title":["Glucocorticoids induce osteonecrosis of the femoral head through the Hippo signaling pathway"],"prefix":"10.1515","volume":"16","author":[{"given":"Yugang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College , No. 278 Baoguang Avenue, Xindu District , Chengdu 610500 , Sichuan , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zechuan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The Second Affiliated Hospital of Chengdu Medical College (Nuclear Industry 416 Hospital) , Chengdu 610057 , Sichuan , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College , No. 278 Baoguang Avenue, Xindu District , Chengdu 610500 , Sichuan , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"2022092006442059538_j_biol-2021-0102_ref_001","doi-asserted-by":"crossref","unstructured":"Wang XS, Zhuang QY, Weng XS, Lin J, Qian WW. Etiological and clinical analysis of osteonecrosis of the femoral head in Chinese patients. Chin Med J (Engl). 2013;126(2):290\u20135.","DOI":"10.3760\/cma.j.issn.0366-6999.20120663"},{"key":"2022092006442059538_j_biol-2021-0102_ref_002","doi-asserted-by":"crossref","unstructured":"Cui L, Zhuang Q, Lin J, Jin J, Zhang K, Cao L, et al. Multicentric epidemiologic study on six thousand three hundred and ninetyfive cases of femoral head osteonecrosis in China. Int Orthop. 2016;40(2):267\u201376.","DOI":"10.1007\/s00264-015-3061-7"},{"key":"2022092006442059538_j_biol-2021-0102_ref_003","doi-asserted-by":"crossref","unstructured":"Griffin M, Iqbal SA, Bayat A. Exploring the application of mesenchymal stem cells in bone repair and regeneration. J Bone Jt Surg Br. 2011;93(4):427\u201334.","DOI":"10.1302\/0301-620X.93B4.25249"},{"key":"2022092006442059538_j_biol-2021-0102_ref_004","doi-asserted-by":"crossref","unstructured":"Dragojevi\u010d J, Logar DB, Komadina R, Marc J. Osteoblastogenesis and adipogenesis are higher in osteoarthritic than in osteoporotic bone tissue. Arch Med Res. 2011;42(5):392\u20137.","DOI":"10.1016\/j.arcmed.2011.08.005"},{"key":"2022092006442059538_j_biol-2021-0102_ref_005","doi-asserted-by":"crossref","unstructured":"Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393(10169):364\u201376.","DOI":"10.1016\/S0140-6736(18)32112-3"},{"key":"2022092006442059538_j_biol-2021-0102_ref_006","doi-asserted-by":"crossref","unstructured":"Maugeri-Sacc\u00e0 M, De Maria R. The Hippo pathway in normal development and cancer. Pharmacol Ther. 2018;186:60\u201372.","DOI":"10.1016\/j.pharmthera.2017.12.011"},{"key":"2022092006442059538_j_biol-2021-0102_ref_007","doi-asserted-by":"crossref","unstructured":"Ou C, Sun Z, He X, Li X, Fan S, Zheng X, et al. Targeting YAP1\/LINC00152\/FSCN1 signaling axis prevents the progression of colorectal cancer. Adv Sci (Weinh). 2019;7(3):1901380.","DOI":"10.1002\/advs.201901380"},{"key":"2022092006442059538_j_biol-2021-0102_ref_008","doi-asserted-by":"crossref","unstructured":"Byun MR, Kim AR, Hwang JH, Sung MK, Lee YK, Hwang BS, et al. Phorbaketal A stimulates osteoblast differentiation through TAZ mediated Runx2 activation. FEBS Lett. 2012;586(8):1086\u201392.","DOI":"10.1016\/j.febslet.2012.03.008"},{"key":"2022092006442059538_j_biol-2021-0102_ref_009","doi-asserted-by":"crossref","unstructured":"Gu K, Fu X, Tian H, Zhang Y, Li A, Wang Y, et al. TAZ promotes the proliferation and osteogenic differentiation of human periodontal ligament stem cells via the p-SMAD3. J Cell Biochem. 2020;121(2):1101\u201313.","DOI":"10.1002\/jcb.29346"},{"key":"2022092006442059538_j_biol-2021-0102_ref_010","doi-asserted-by":"crossref","unstructured":"Hong W, Guan KL. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23(7):785\u201393.","DOI":"10.1016\/j.semcdb.2012.05.004"},{"key":"2022092006442059538_j_biol-2021-0102_ref_011","unstructured":"Dong L, Li L. Large tumor suppressor gene 2-mediated Hippo signaling pathway reglates the biological behavior of mesenchymal stem cells in vitro. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019;31(9):1143\u20138."},{"key":"2022092006442059538_j_biol-2021-0102_ref_012","doi-asserted-by":"crossref","unstructured":"Kuang MJ, Zhang KH, Qiu J, Wang AB, Che WW, Li XM, et al. Exosomal miR-365a-5p derived from HUC-MSCs regulates osteogenesis in GIONFH through the Hippo signaling pathway. Mol Ther Nucleic Acids. 2020;23:565\u201376.","DOI":"10.1016\/j.omtn.2020.12.006"},{"key":"2022092006442059538_j_biol-2021-0102_ref_013","doi-asserted-by":"crossref","unstructured":"Shahdadfar A, Fr\u00f8nsdal K, Haug T, Reinholt FP, Brinchmann JE. In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability. Stem Cell. 2005;23(9):1357\u201366.","DOI":"10.1634\/stemcells.2005-0094"},{"key":"2022092006442059538_j_biol-2021-0102_ref_014","doi-asserted-by":"crossref","unstructured":"Li X, Jin L, Cui Q, Wang GJ, Balian G. Steroid effects on osteogenesis through mesenchymal cell gene expression. Osteoporos Int. 2005;16(1):101\u20138.","DOI":"10.1007\/s00198-004-1649-7"},{"key":"2022092006442059538_j_biol-2021-0102_ref_015","doi-asserted-by":"crossref","unstructured":"Murata M, Kumagai K, Miyata N, Osaki M, Shindo H. Osteonecrosis in stroke-prone spontaneously hypertensive rats: effect of glucocorticoid. J Orthop Sci. 2007;12(3):289\u201395.","DOI":"10.1007\/s00776-007-1129-y"},{"key":"2022092006442059538_j_biol-2021-0102_ref_016","doi-asserted-by":"crossref","unstructured":"Zou W, Yang S, Zhang T, Sun H, Wang Y, Xue H, et al. Hypoxia enhances glucocorticoid-induced apoptosis and cell cycle arrest via the PI3K\/Akt signaling pathway in osteoblastic cells. J Bone Min Metab. 2015;33(6):615\u201324.","DOI":"10.1007\/s00774-014-0627-1"},{"key":"2022092006442059538_j_biol-2021-0102_ref_017","doi-asserted-by":"crossref","unstructured":"Zhang WL, Chi CT, Meng XH, Liang SD. miRNA-15a-5p facilitates the bone marrow stem cell apoptosis of femoral head necrosis through the Wnt\/\u03b2-catenin\/PPAR\u03b3 signaling pathway. Mol Med Rep. 2019;19(6):4779\u201387.","DOI":"10.3892\/mmr.2019.10130"},{"key":"2022092006442059538_j_biol-2021-0102_ref_018","doi-asserted-by":"crossref","unstructured":"Nie Z, Chen S, Deng S, Long L, Peng P, Gao M, et al. Gene expression profiling of osteoblasts subjected to dexamethasone-induced apoptosis with\/without GSK3\u03b2-shRNA. Biochem Biophys Res Commun. 2018;506(1):41\u20137.","DOI":"10.1016\/j.bbrc.2018.10.043"},{"key":"2022092006442059538_j_biol-2021-0102_ref_019","doi-asserted-by":"crossref","unstructured":"Wu X, Yang S, Wang H, Meng C, Xu W, Duan D, et al. G-CSF\/SCF exert beneficial effects via anti-apoptosis in rabbits with steroid-associated osteonecrosis. Exp Mol Pathol. 2013;94(1):247\u201354.","DOI":"10.1016\/j.yexmp.2012.06.003"},{"key":"2022092006442059538_j_biol-2021-0102_ref_020","doi-asserted-by":"crossref","unstructured":"Hao C, Yang S, Xu W, Shen JK, Ye S, Liu X, et al. MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3. Sci Rep. 2016;6:22599.","DOI":"10.1038\/srep22599"},{"key":"2022092006442059538_j_biol-2021-0102_ref_021","doi-asserted-by":"crossref","unstructured":"Pengde K, Fuxing P, Bin S, Jing Y, Jingqiu C. Lovastatin inhibits adipogenesis and prevents osteonecrosis in steroid-treated rabbits. Jt Bone Spine. 2008;75(6):696\u2013701.","DOI":"10.1016\/j.jbspin.2007.12.008"},{"key":"2022092006442059538_j_biol-2021-0102_ref_022","doi-asserted-by":"crossref","unstructured":"Sun ZB, Wang JW, Xiao H, Zhang QS, Kan WS, Mo FB, et al. Icariin may benefit the mesenchymal stem cells of patients with steroid-associated osteonecrosis by ABCB1-promoter demethylation: a preliminary study. Osteoporos Int. 2015;26(1):187\u201397.","DOI":"10.1007\/s00198-014-2809-z"},{"key":"2022092006442059538_j_biol-2021-0102_ref_023","doi-asserted-by":"crossref","unstructured":"Saucedo LJ, Edgar BA. Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007 Aug;8(8):613\u201321.","DOI":"10.1038\/nrm2221"},{"key":"2022092006442059538_j_biol-2021-0102_ref_024","doi-asserted-by":"crossref","unstructured":"Sohn BH, Shim JJ, Kim SB, Jang KY, Kim SM, Kim JH, et al. Inactivation of Hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin Cancer Res. 2016;22(5):1256\u201364.","DOI":"10.1158\/1078-0432.CCR-15-1447"},{"key":"2022092006442059538_j_biol-2021-0102_ref_025","doi-asserted-by":"crossref","unstructured":"Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al. Role of YAP\/TAZ in mechanotransduction. Nature. 2011;474(7350):179\u201383.","DOI":"10.1038\/nature10137"},{"key":"2022092006442059538_j_biol-2021-0102_ref_026","doi-asserted-by":"crossref","unstructured":"Murakami M, Nakagawa M, Olson EN, Nakagawa O. A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome. Proc Natl Acad Sci USA. 2005;102(50):18034\u20139.","DOI":"10.1073\/pnas.0509109102"},{"key":"2022092006442059538_j_biol-2021-0102_ref_027","doi-asserted-by":"crossref","unstructured":"Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309(5737):1074\u20138.","DOI":"10.1126\/science.1110955"},{"key":"2022092006442059538_j_biol-2021-0102_ref_028","doi-asserted-by":"crossref","unstructured":"Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008;20(6):638\u201346.","DOI":"10.1016\/j.ceb.2008.10.001"}],"container-title":["Open Life Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/biol-2021-0102\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/biol-2021-0102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T21:15:27Z","timestamp":1726002927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/biol-2021-0102\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,1]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,20]]},"published-print":{"date-parts":[[2021,1,20]]}},"alternative-id":["10.1515\/biol-2021-0102"],"URL":"https:\/\/doi.org\/10.1515\/biol-2021-0102","relation":{},"ISSN":["2391-5412"],"issn-type":[{"value":"2391-5412","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,1]]}}}