{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T11:04:21Z","timestamp":1793876661508,"version":"4.7.0"},"reference-count":36,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T00:00:00Z","timestamp":1560297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National High Technology Research and Development Program of China","award":["2011AA09070109"],"award-info":[{"award-number":["2011AA09070109"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81750110548"],"award-info":[{"award-number":["81750110548"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Plan of Innovation Action in Shanghai","award":["15410722500"],"award-info":[{"award-number":["15410722500"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>A recent study reported the expression of receptor activator of nuclear factor-\u03baB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-\u03baB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL.<\/jats:p>","DOI":"10.3390\/jcm8060836","type":"journal-article","created":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T10:55:19Z","timestamp":1560336919000},"page":"836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4115-9918","authenticated-orcid":false,"given":"Jeevithan","family":"Elango","sequence":"first","affiliation":[{"name":"Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2234-2274","authenticated-orcid":false,"given":"Saeed Ur","family":"Rahman","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Centre in Biomedical Materials (IRCBM), COMSATS University Islamabad, Lahore Campus, Punjab 54000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Henrotin","sequence":"additional","affiliation":[{"name":"Bone and Cartilage Research Unit, Arthrop\u00f4le Li\u00e8ge, University of Li\u00e8ge, CHU Sart-Tilman 4000, Liege, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Eduardo Mat\u00e9 S\u00e1nchez","family":"de Val","sequence":"additional","affiliation":[{"name":"Department of Biomaterials Engineering, Universidad Cat\u00f3lica San Antonio de Murcia, 30107 Guadalupe, Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Wang","sequence":"additional","affiliation":[{"name":"Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Huaihai Institute of Technology, Lianyungang 222005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-8582","authenticated-orcid":false,"given":"Wenhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Marine Bio-Pharmacology, College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China"},{"name":"National R&amp;D Branch Center for Freshwater Aquatic Products Processing Technology (Shanghai), Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S8756-3282(99)00214-8","article-title":"Loalization of RANKL (receptor activator of NFkB ligand) mRNA and protein in skeletal and extraskeletal tissues","volume":"25","author":"Kartsogiannis","year":"1999","journal-title":"Bone"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmed.2005.11.007","article-title":"RANKL-RANK signaling in osteoclastogenesis and bone disease","volume":"12","author":"Wada","year":"2006","journal-title":"Trends Mol. 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