{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T23:01:21Z","timestamp":1787871681459,"version":"build-2784847793"},"reference-count":34,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades, Spain, FEDER","doi-asserted-by":"publisher","award":["SAF2017-85806-R"],"award-info":[{"award-number":["SAF2017-85806-R"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Parathyroid hormone-related protein (PTHrP) C-terminal peptides regulate the metabolism of bone cells. PHTrP [107\u2013111] (osteostatin) promotes bone repair in animal models of bone defects and prevents bone erosion in inflammatory arthritis. In addition to its positive effects on osteoblasts, osteostatin may inhibit bone resorption. The aim of this study was to determine the effects of osteostatin on human osteoclast differentiation and function. We used macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor \u03baB ligand (RANKL) to induce the osteoclast differentiation of adherent human peripheral blood mononuclear cells. Tartrate-resistant acid phosphatase (TRAP) staining was performed for the detection of the osteoclasts. The function of mature osteoclasts was assessed with a pit resorption assay. Gene expression was evaluated with qRT-PCR, and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation was studied by immunofluorescence. We observed that osteostatin (100, 250 and 500 nM) decreased the differentiation of osteoclasts in a concentration-dependent manner, but it did not modify the resorptive ability of mature osteoclasts. In addition, osteostatin decreased the mRNA levels of cathepsin K, osteoclast associated Ig-like receptor (OSCAR) and NFATc1. The nuclear translocation of the master transcription factor in osteoclast differentiation NFATc1 was reduced by osteostatin. Our results suggest that the anti-resorptive effects of osteostatin may be dependent on the inhibition of osteoclastogenesis. This study has shown that osteostatin controls human osteoclast differentiation in vitro through the downregulation of NFATc1.<\/jats:p>","DOI":"10.3390\/ijms23158551","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T21:01:24Z","timestamp":1659387684000},"page":"8551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Osteostatin Inhibits M-CSF+RANKL-Induced Human Osteoclast Differentiation by Modulating NFATc1"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2217-8817","authenticated-orcid":false,"given":"Lidia","family":"Ib\u00e1\u00f1ez","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Cardenal Herrera-CEU Universities, 46115 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"N\u00e1cher-Juan","sequence":"additional","affiliation":[{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3800-6048","authenticated-orcid":false,"given":"Mar\u00eda Carmen","family":"Terencio","sequence":"additional","affiliation":[{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Ferr\u00e1ndiz","sequence":"additional","affiliation":[{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5459-6407","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Alcaraz","sequence":"additional","affiliation":[{"name":"Interuniversity Research Institute for Molecular Recognition and Technological Development (IDM), Polytechnic University of Valencia, University of Valencia, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1126\/science.289.5484.1508","article-title":"Therapeutic approaches to bone diseases","volume":"289","author":"Rodan","year":"2000","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S8756-3282(96)00221-9","article-title":"PTHrP (1\u201336) as a skeletal anabolic agent for the treatment of osteoporosis","volume":"19","author":"Stewart","year":"1996","journal-title":"Bone"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1089\/ten.tea.2009.0355","article-title":"Role of the N- and C-terminal fragments of parathyroid-hormone-related protein as putative therapies to improve bone regeneration under high glucocorticoid treatment","volume":"16","author":"Lozano","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1002\/jcp.22902","article-title":"Comparison of the skeletal effects induced by daily administration of PTHrP (1\u201336) and PTHrP (107\u2013139) to ovariectomized mice","volume":"227","author":"Lozano","year":"2012","journal-title":"J. Cell. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1359\/jbmr.1999.14.6.915","article-title":"Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein","volume":"14","author":"Cornish","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1210\/endo-129-4-1762","article-title":"A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts","volume":"129","author":"Fenton","year":"1991","journal-title":"Endocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcp.1041550102","article-title":"Long-term culture of disaggregated rat osteoclasts: Inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP [107\u2013139]","volume":"155","author":"Fenton","year":"1993","journal-title":"J. Cell. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1210\/endo-129-6-3424","article-title":"A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP [107\u2013111]","volume":"129","author":"Fenton","year":"1991","journal-title":"Endocrinology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.bbrc.2022.02.085","article-title":"Osteostatin improves the osteogenic differentiation of mesenchymal stem cells and enhances angiogenesis through HIF-1\u03b1 under hypoxia conditions in vitro","volume":"606","author":"Wu","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","first-page":"624","article-title":"Anti-senescence and anti-inflammatory effects of the C-terminal moiety of PTHrP peptides in OA osteoblasts","volume":"172","author":"Platas","year":"2017","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rodriguez-de la Rosa, L., Lopez-Herradon, A., Portal-Nu\u00f1ez, S., Murillo-Cuesta, S., Lozano, D., Cediel, R., Varela-Nieto, I., and Esbrit, P. (2014). Treatment with N- and C-terminal peptides of parathyroid hormone-related protein partly compensate the skeletal abnormalities in IGF-1 deficient mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087536"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.actbio.2012.03.014","article-title":"Osteostatin-loaded onto mesoporous ceramics improves the early phase of bone regeneration in a rabbit osteopenia model","volume":"8","author":"Lozano","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3307","DOI":"10.1016\/j.actbio.2014.03.025","article-title":"Parathyroid hormone-related protein (107\u2013111) improves the bone regeneration potential of gelatin-glutaraldehyde biopolymer-coated hydroxyapatite","volume":"10","author":"Lozano","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8564","DOI":"10.1016\/j.biomaterials.2010.07.103","article-title":"The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model","volume":"31","author":"Trejo","year":"2010","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"N\u00e1cher-Juan, J., Terencio, M.C., Alcaraz, M.J., and Ferr\u00e1ndiz, M.L. (2019). Osteostatin inhibits collagen-induced arthritis by regulation of immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163845"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1126\/science.289.5484.1504","article-title":"Bone resorption by osteoclasts","volume":"289","author":"Teitelbaum","year":"2000","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1002\/jcb.21553","article-title":"The osteoclast: A multinucleated, hematopoietic-origin, bone-resorbing osteoimmune cell","volume":"102","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/15216540500137669","article-title":"RANKing intracellular signaling in osteoclasts","volume":"57","author":"Feng","year":"2005","journal-title":"IUBMB Life"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1146\/annurev.immunol.24.021605.090646","article-title":"Osteoimmunology: Interplay between the immune system and bone metabolism","volume":"24","author":"Walsh","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/jbmr.5650090411","article-title":"Carboxyl-terminal parathyroid hormone-related protein inhibits bone resorption by isolated chicken osteoclasts","volume":"9","author":"Fenton","year":"1994","journal-title":"J. Bone Miner. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF00298996","article-title":"Lack of significant effect of carboxyl-terminal parathyroid hormone-related peptide fragments on isolated rat and chick osteoclasts","volume":"57","author":"Murrills","year":"1995","journal-title":"Calcif. Tissue Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.bone.2006.09.023","article-title":"The molecular understanding of osteoclast differentiation","volume":"40","author":"Asagiri","year":"2007","journal-title":"Bone"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/jcb.240540203","article-title":"Tartrate resistant acid phosphatase activity in rat cultured osteoclasts is inhibited by a carboxyl terminal peptide (osteostatin) from parathyroid hormone-related protein","volume":"54","author":"Zheng","year":"1994","journal-title":"J. Cell. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1210\/endo.138.3.4990","article-title":"Parathyroid hormone-related protein-(107\u2013139) inhibits bone resorption in vivo","volume":"138","author":"Cornish","year":"1997","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1210\/endo.131.6.1306984","article-title":"Human parathyroid hormone-related peptide-(107\u2013111) does not inhibit bone resorption in neonatal mouse calvariae","volume":"131","author":"Sone","year":"1992","journal-title":"Endocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1007\/s002239900359","article-title":"PTHrP (107\u2013111) inhibits in vivo resorption that was stimulated by PTHrP (1\u201334) when applied intermittently to neonatal mice","volume":"61","author":"Lewinson","year":"1997","journal-title":"Calcif. Tissue Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1084\/jem.190.12.1741","article-title":"Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappa B (RANK) receptors","volume":"190","author":"Arai","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","article-title":"Osteoclast differentiation and activation","volume":"423","author":"Boyle","year":"2003","journal-title":"Nature"},{"key":"ref_29","first-page":"147","article-title":"Osteoclast receptors and signaling","volume":"73","author":"Teti","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.bbrc.2007.06.017","article-title":"Traf6 ubiquitin ligase is essential for RANKL signaling and osteoclast differentiation","volume":"359","author":"Lamothe","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1124\/pr.114.009464","article-title":"International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors\u2014Family B G protein-coupled receptors","volume":"67","author":"Gardella","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1210\/endo.142.7.8276","article-title":"C-terminal parathyroid hormone-related protein (PTHrP) (107\u2013139) stimulates intracellular Ca2+ through a receptor different from the type 1 PTH\/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells","volume":"142","author":"Valin","year":"2001","journal-title":"Endocrinology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1111\/bcp.13766","article-title":"Osteoanabolic and dual action drugs","volume":"85","author":"Tabacco","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8551\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:01:00Z","timestamp":1760140860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/15\/8551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,1]]},"references-count":34,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23158551"],"URL":"https:\/\/doi.org\/10.3390\/ijms23158551","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,1]]}}}