{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T20:03:09Z","timestamp":1781899389846,"version":"3.54.5"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T00:00:00Z","timestamp":1540252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T00:00:00Z","timestamp":1544745600000},"content-version":"vor","delay-in-days":52,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR066782"],"award-info":[{"award-number":["R01AR066782"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR068835"],"award-info":[{"award-number":["R01AR068835"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AR061399"],"award-info":[{"award-number":["R01AR061399"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08DE026805"],"award-info":[{"award-number":["K08DE026805"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell-1 in endochondral ossification by investigating Nell-1-specific inactivation in Col2\u03b11-expressing cell lineages. Nell-1flox\/flox; Col2\u03b11-Cre+ (Nell-1Col2\u03b11KO) mice were generated for comprehensive analysis. Nell-1Col2\u03b11KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell-1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell-1Col2\u03b11KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV\/TV), trabecular number\/thickness, cortical volume\/thickness\/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and\/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro-CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col-2, Col-10, and fewer BrdU-positive chondrocytes were observed in thinner Nell-1Col2\u03b11KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched-1, PTHrP, and PTHrP receptor. Primary Nell-1Col2\u03b11KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh-PTHrP signaling molecules can be partially rescued by exogenous Nell-1 protein. Moreover, intranuclear Gli-1 protein and gene expression of the Gli-1 downstream target genes, Hip-1 and N-Myc, were also significantly decreased with Nell-1 inactivation. Notably, the rescue effects were diminished\/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell-1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte-specific Nell-1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh-PTHrP feedback loop. \u00a9 2018 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3615","type":"journal-article","created":{"date-parts":[[2018,10,24]],"date-time":"2018-10-24T01:22:32Z","timestamp":1540344152000},"page":"533-546","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis"],"prefix":"10.1093","volume":"34","author":[{"given":"Huichuan","family":"Qi","sequence":"first","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"},{"name":"Department of OrthodonticsSchool and Hospital of StomatologyJilin UniversityChangchunJilinPR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Kil","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin","family":"Ha","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of OrthodonticsAffiliated Hospital of StomatologyMedical CollegeZhejiang UniversityHangzhouZhejiangPR China"},{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin Chuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengliu","family":"Yu","sequence":"additional","affiliation":[{"name":"Center of StomatologyChina-Japan Friendship Hospital2nd Yinghuayuan East StreetChaoyang DistrictBeijingPR China"},{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasamin","family":"Mohazeb","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Azer","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd","family":"Baik","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Hee","family":"Kwak","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Ting","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Growth and DevelopmentSection of OrthodonticsSchool of DentistryUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of OrthodonticsSchool and Hospital of StomatologyJilin UniversityChangchunJilinPR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia","family":"Soo","sequence":"additional","affiliation":[{"name":"Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research CenterUniversity of CaliforniaLos AngelesCAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,10,23]]},"reference":[{"issue":"6","key":"2024021014524518500_jbmr3615-bib-0001","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1172\/JCI15375","article-title":"Craniosynostosis in transgenic mice overexpressing Nell-1","volume":"110","author":"Zhang","year":"2002","journal-title":"J Clin 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