{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T19:41:01Z","timestamp":1769715661110,"version":"3.49.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2010,10,11]],"date-time":"2010-10-11T00:00:00Z","timestamp":1286755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mesenchymal stem cell commitment to an osteoprogenitor lineage requires the activity of Runx2, a molecule implicated in the etiopathology of multiple congenital craniofacial anomalies. Through promoter analyses, we have recently identified a new direct transcriptional target of Runx2, Nell-1, a craniosynostosis (CS)\u2013associated molecule with potent osteogenic properties. This study investigated the mechanistic and functional relationship between Nell-1 and Runx2 in regulating osteoblast differentiation. The results showed that spatiotemporal distribution and expression levels of Nell-1 correlated closely with those of endogenous Runx2 during craniofacial development. Phenotypically, cross-mating Nell-1 overexpression transgenic (CMV-Nell-1) mice with Runx2 haploinsufficient (Runx2+\/\u2212) mice partially rescued the calvarial defects in the cleidocranial dysplasia (CCD)\u2013like phenotype of Runx2+\/\u2212 mice, whereas Nell-1 protein induced mineralization and bone formation in Runx2+\/\u2212 but not Runx2\u2212\/\u2212 calvarial explants. Runx2-mediated osteoblastic gene expression and\/or mineralization was severely reduced by Nell-1 siRNA oligos transfection into Runx2+\/+ newborn mouse calvarial cells (NMCCs) or in N-ethyl-N-nitrosourea (ENU)\u2013induced Nell-1\u2212\/\u2212 NMCCs. Meanwhile, Nell-1 overexpression partially rescued osteoblastic gene expression but not mineralization in Runx2 null (Runx2\u2212\/\u2212) NMCCs. Mechanistically, irrespective of Runx2 genotype, Nell-1 signaling activates ERK1\/2 and JNK1 mitogen-activated protein kinase (MAPK) pathways in NMCCs and enhances Runx2 phosphorylation and activity when Runx2 is present. Collectively, these data demonstrate that Nell-1 is a critical downstream Runx2 functional mediator insofar as Runx2-regulated Nell-1 promotes osteoblastic differentiation through, in part, activation of MAPK and enhanced phosphorylation of Runx2, and Runx2 activity is significantly reduced when Nell-1 is blocked or absent. \u00a9 2011 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.267","type":"journal-article","created":{"date-parts":[[2010,10,11]],"date-time":"2010-10-11T19:31:22Z","timestamp":1286825482000},"page":"777-791","source":"Crossref","is-referenced-by-count":76,"title":["Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in <i>Runx2<\/i>\n                  <i>+<\/i>\/<i>\u2212<\/i> mice"],"prefix":"10.1093","volume":"26","author":[{"given":"Xinli","family":"Zhang","sequence":"first","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, 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Ridge, TN, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Jin","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haofu","family":"Lee","sequence":"additional","affiliation":[{"name":"Section of Orthodontics, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Dental and Craniofacial Research Institute, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia","family":"Shen","sequence":"additional","affiliation":[{"name":"Dental and Craniofacial Research Institute, University of California Los Angeles, Los Angeles, CA, 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