{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:40:47Z","timestamp":1790772047911,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T00:00:00Z","timestamp":1658016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["F30DE030675"],"award-info":[{"award-number":["F30DE030675"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R01DE029181"],"award-info":[{"award-number":["R01DE029181"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R01DE026666"],"award-info":[{"award-number":["R01DE026666"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"NIH\/NIDCR","doi-asserted-by":"publisher","award":["R01DE030630"],"award-info":[{"award-number":["R01DE030630"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cranial base contains a special type of growth plate termed the synchondrosis, which functions as the growth center of the skull. The synchondrosis is composed of bidirectional opposite-facing layers of resting, proliferating, and hypertrophic chondrocytes, and lacks the secondary ossification center. In long bones, the resting zone of the epiphyseal growth plate houses a population of parathyroid hormone-related protein (PTHrP)-expressing chondrocytes that contribute to the formation of columnar chondrocytes. Whether PTHrP+ chondrocytes in the synchondrosis possess similar functions remains undefined. Using Pthrp-mCherry knock-in mice, we found that PTHrP+ chondrocytes predominantly occupied the lateral wedge-shaped area of the synchondrosis, unlike those in the femoral growth plate that reside in the resting zone within the epiphysis. In vivo cell-lineage analyses using a tamoxifen-inducible Pthrp-creER line revealed that PTHrP+ chondrocytes failed to establish columnar chondrocytes in the synchondrosis. Therefore, PTHrP+ chondrocytes in the synchondrosis do not possess column-forming capabilities, unlike those in the resting zone of the long bone growth plate. These findings support the importance of the secondary ossification center within the long bone epiphysis in establishing the stem cell niche for PTHrP+ chondrocytes, the absence of which may explain the lack of column-forming capabilities of PTHrP+ chondrocytes in the cranial base synchondrosis.<\/jats:p>","DOI":"10.3390\/ijms23147873","type":"journal-article","created":{"date-parts":[[2022,7,17]],"date-time":"2022-07-17T22:57:06Z","timestamp":1658098626000},"page":"7873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cranial Base Synchondrosis Lacks PTHrP-Expressing Column-Forming Chondrocytes"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1472-7502","authenticated-orcid":false,"given":"Shawn A.","family":"Hallett","sequence":"first","affiliation":[{"name":"Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis","family":"Herzog","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Arbiv","sequence":"additional","affiliation":[{"name":"Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanida","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3771-8230","authenticated-orcid":false,"given":"Noriaki","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/35076601","article-title":"Genetics of craniofacial development and malformation","volume":"2","author":"Wilkie","year":"2001","journal-title":"Nat. Rev. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rengasamy Venugopalan, S., and van Otterloo, E. (2021). The Skull\u2019s Girder: A Brief Review of the Cranial Base. J. Dev. Biol., 9.","DOI":"10.3390\/jdb9010003"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ydbio.2008.07.016","article-title":"Development and tissue origins of the mammalian cranial base","volume":"322","author":"Iseki","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1097\/00006534-199911000-00001","article-title":"Molecular diagnosis of bilateral coronal synostosis","volume":"104","author":"Mullikcn","year":"1999","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1097\/SCS.0000000000000386","article-title":"Premature closure of the spheno-occipital synchondrosis in pfeiffer syndrome: A link to midface hypoplasia","volume":"25","author":"Paliga","year":"2015","journal-title":"J. Cranio. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1016\/j.joms.2013.11.015","article-title":"The Spheno-occipital synchondrosis fuses prematurely in patients with crouzon syndrome and midface hypoplasia compared with age- and gender-matched controls","volume":"72","author":"Tahiri","year":"2014","journal-title":"J. Oral. Maxillofac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R50","DOI":"10.1093\/hmg\/ddv228","article-title":"New insights into craniofacial malformations","volume":"24","author":"Twigg","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2147\/CCIDE.S134303","article-title":"Developing Class III malocclusions: Challenges and solutions","volume":"10","author":"Zere","year":"2018","journal-title":"Clin. Cosmet. Investig. Dent."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1055\/s-0034-1390172","article-title":"Le fort i maxillary advancement using distraction osteogenesis","volume":"28","author":"Combs","year":"2014","journal-title":"Sem. Plast. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1097\/00006534-196904000-00003","article-title":"Surgical correction of small or retrodisplaced maxillae: The \u201cdish-face\u201d deformity","volume":"43","author":"Obwegeser","year":"1969","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"706","DOI":"10.3389\/fcell.2020.00706","article-title":"New Insights Into Cranial Synchondrosis Development: A Mini Review","volume":"8","author":"Funato","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1080\/00016350510019847","article-title":"Cranial base in craniofacial development: Developmental features, influence on facial growth, anomaly, and molecular basis","volume":"63","author":"Nie","year":"2005","journal-title":"Acta Odontol. Scand."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1177\/0022034516651823","article-title":"Developmental regulation of the growth plate and cranial synchondrosis","volume":"95","author":"Wei","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7817","DOI":"10.3390\/ijms23147817","article-title":"Cranial Base Synchondrosis: Skull Chondrocytes at the Hub","volume":"23","author":"Hallett","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hallett, S.A., Ono, W., and Ono, N. (2019). Growth plate chondrocytes: Skeletal development, growth and beyond. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236009"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e55212","DOI":"10.7554\/eLife.55212","article-title":"Secondary ossification center induces and protects growth plate structure","volume":"9","author":"Xie","year":"2020","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41586-019-0989-6","article-title":"A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate","volume":"567","author":"Newton","year":"2019","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41586-018-0662-5","article-title":"Resting zone of the growth plate houses a unique class of skeletal stem cells","volume":"563","author":"Mizuhashi","year":"2018","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation","volume":"13","author":"Hammerschmidt","year":"1999","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1101\/gad.8.3.277","article-title":"Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene","volume":"8","author":"Karaplis","year":"1994","journal-title":"Genes Dev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/(SICI)1097-0185(19990801)255:4<452::AID-AR10>3.0.CO;2-E","article-title":"Differential responses to parathyroid hormone-related protein (PTHrP) deficiency in the various craniofacial cartilages","volume":"255","author":"Suda","year":"1999","journal-title":"Anat. Rec."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1148\/radiology.196.3.7644639","article-title":"Suture closure in the human chondrocranium: CT assessment","volume":"196","author":"Madeline","year":"1995","journal-title":"Radio"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1148\/radiology.196.3.7644640","article-title":"Postnatal development of the central skull base: Normal variants","volume":"196","author":"Madeline","year":"1995","journal-title":"Radio"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1359\/JBMR.051005","article-title":"Initial Characterization of PTH-Related Protein Gene-Driven lacZ Expression in the Mouse","volume":"21","author":"Chen","year":"2006","journal-title":"J. Bone Min. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lui, J.C., Jee, Y.H., Garrison, P., Iben, J.R., Yue, S., Ad, M., Nguyen, Q., Kikani, B., Wakabayashi, Y., and Baron, J. (2018). Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005263"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3389\/fphys.2017.00697","article-title":"Postnatal craniofacial skeletal development of female C57BL\/6NCrl mice","volume":"8","author":"Wei","year":"2017","journal-title":"Front. Phys."},{"key":"ref_28","first-page":"831","article-title":"Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases","volume":"96","author":"Martin","year":"2016","journal-title":"Phys. Rev."},{"key":"ref_29","unstructured":"Thakker, R.W., Whyte, M.P., Eisman, J.A., and Igarashi, T. (2013). Integrating endocrine and paracrine influences on bone: Lessons from parathyroid hormone and parathyroid hormone-related protein. Genetics of Bone Biology and Skeletal Disease, Academic Press."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1001\/jama.2016.11136","article-title":"Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: A randomized clinical trial","volume":"316","author":"Miller","year":"2016","journal-title":"JAMA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7873\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:52:25Z","timestamp":1760140345000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7873"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,17]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147873"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147873","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,17]]}}}