The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification
The developing long bone is a model of endochondral ossification that displays the morphological layers of chondrocytes toward the ossification center of the diaphysis. Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiati...
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| creator | Laurie, Lindsay E Kokubo, Hiroki Nakamura, Masataka Saga, Yumiko Funato, Noriko |
| description | The developing long bone is a model of endochondral ossification that displays the morphological layers of chondrocytes toward the ossification center of the diaphysis. Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis. |
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Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0150263</identifier><identifier>PMID: 26918743</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Basic Helix-Loop-Helix Transcription Factors - physiology ; Biocompatibility ; Biology and Life Sciences ; Biomedical materials ; Bone and Bones - embryology ; Bone and Bones - metabolism ; Bone and Bones - pathology ; Bones ; Cartilage ; Cbfa-1 protein ; Cell Line ; Chondrocytes ; Chondrogenesis ; Core Binding Factor Alpha 1 Subunit - antagonists & inhibitors ; Core Binding Factor Alpha 1 Subunit - physiology ; Deoxyribonucleic acid ; Diaphyses ; Diaphysis ; Differentiation ; DNA ; Down-Regulation ; Endochondral bone ; Endochondral ossification ; Epiphysis ; Female ; Femur ; Gene expression ; Genes, Reporter ; Genetic aspects ; Growth Plate - metabolism ; Hedgehog protein ; Hedgehog Proteins - biosynthesis ; Hedgehog Proteins - deficiency ; Hedgehog Proteins - genetics ; Hedgehog Proteins - physiology ; Helix-loop-helix proteins ; Helix-loop-helix proteins (basic) ; Kinases ; Laboratory animals ; Limb Deformities, Congenital - genetics ; Long bone ; Male ; Medicine and Health Sciences ; Mice ; Mice, Transgenic ; Mimicry ; Ossification ; Osteoblastogenesis ; Osteogenesis ; Osteogenesis - genetics ; Osteogenesis - physiology ; Osteopontin - biosynthesis ; Osteopontin - genetics ; Osteoprogenitor cells ; Phenotype ; Physiological aspects ; Primordia ; Promoter Regions, Genetic - genetics ; Real-Time Polymerase Chain Reaction ; Recombinant Fusion Proteins - metabolism ; Repressor Proteins - genetics ; Rodents ; Signal Transduction - physiology ; Transcription factors ; Transcriptional Activation ; Transfection ; Twist-Related Protein 1 - genetics</subject><ispartof>PloS one, 2016-02, Vol.11 (2), p.e0150263-e0150263</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Laurie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Laurie et al 2016 Laurie et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-e771277d569d71b46708fdf10b8729ceb1e3ac34bcec02aacd13c04f2ddcdbad3</citedby><cites>FETCH-LOGICAL-c758t-e771277d569d71b46708fdf10b8729ceb1e3ac34bcec02aacd13c04f2ddcdbad3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769249/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769249/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26918743$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Kim, Jung-Eun</contributor><creatorcontrib>Laurie, Lindsay E</creatorcontrib><creatorcontrib>Kokubo, Hiroki</creatorcontrib><creatorcontrib>Nakamura, Masataka</creatorcontrib><creatorcontrib>Saga, Yumiko</creatorcontrib><creatorcontrib>Funato, Noriko</creatorcontrib><title>The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The developing long bone is a model of endochondral ossification that displays the morphological layers of chondrocytes toward the ossification center of the diaphysis. Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis.</description><subject>Animals</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Basic Helix-Loop-Helix Transcription Factors - physiology</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>Bone and Bones - embryology</subject><subject>Bone and Bones - metabolism</subject><subject>Bone and Bones - pathology</subject><subject>Bones</subject><subject>Cartilage</subject><subject>Cbfa-1 protein</subject><subject>Cell Line</subject><subject>Chondrocytes</subject><subject>Chondrogenesis</subject><subject>Core Binding Factor Alpha 1 Subunit - antagonists & inhibitors</subject><subject>Core Binding Factor Alpha 1 Subunit - physiology</subject><subject>Deoxyribonucleic acid</subject><subject>Diaphyses</subject><subject>Diaphysis</subject><subject>Differentiation</subject><subject>DNA</subject><subject>Down-Regulation</subject><subject>Endochondral bone</subject><subject>Endochondral ossification</subject><subject>Epiphysis</subject><subject>Female</subject><subject>Femur</subject><subject>Gene expression</subject><subject>Genes, Reporter</subject><subject>Genetic aspects</subject><subject>Growth Plate - metabolism</subject><subject>Hedgehog protein</subject><subject>Hedgehog Proteins - biosynthesis</subject><subject>Hedgehog Proteins - deficiency</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - physiology</subject><subject>Helix-loop-helix proteins</subject><subject>Helix-loop-helix proteins (basic)</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Limb Deformities, Congenital - genetics</subject><subject>Long bone</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mimicry</subject><subject>Ossification</subject><subject>Osteoblastogenesis</subject><subject>Osteogenesis</subject><subject>Osteogenesis - genetics</subject><subject>Osteogenesis - physiology</subject><subject>Osteopontin - biosynthesis</subject><subject>Osteopontin - genetics</subject><subject>Osteoprogenitor cells</subject><subject>Phenotype</subject><subject>Physiological aspects</subject><subject>Primordia</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Repressor Proteins - genetics</subject><subject>Rodents</subject><subject>Signal Transduction - physiology</subject><subject>Transcription factors</subject><subject>Transcriptional Activation</subject><subject>Transfection</subject><subject>Twist-Related Protein 1 - genetics</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01r3DAQhk1padK0_6C0hkJpD95KsizZl0IISWMILGy3vfQgZH2sFbzSVrKX9N9XzjphXXIoOkiMnnlHM5pJkrcQLGBO4ZdbN3jLu8XOWbUAsACI5M-SU1jlKCMI5M-PzifJqxBuASjykpCXyQkiFSwpzk-TX-tWpWvPbRDe7HrjbHrFRe98es2thGkd0truXbdXMh7S1WDvUFa3bbZSm6HjfTRfWulE66z0vEuXIRhtBB-VXicvNO-CejPtZ8mPq8v1xXV2s_xWX5zfZIIWZZ8pSiGiVBakkhQ2mFBQaqkhaEqKKqEaqHIuctwIJQDiXEiYC4A1klLIhsv8LHl_0N11LrCpLoHBe11IchKJ-kBIx2_Zzpst93-Y44bdG5zfMO57IzrFRAO0qohWBSwwKgQnGmMsSl2UTdNoHLW-TtGGZqukULaPic9E5zfWtGzj9gxTUiFcRYFPk4B3vwcVerY1Qaiu41a5YXw3qQgiGJUR_fAP-nR2E7XhMQFjtYtxxSjKzuPbI0FLEKnFE1RcUm2NiE2kTbTPHD7PHCLTq7t-w4cQWP199f_s8uec_XjEtop3fRtcN4wtE-YgPoDCuxC80o9FhoCNM_BQDTbOAJtmILq9O_6gR6eHps__Al7UAg4</recordid><startdate>20160226</startdate><enddate>20160226</enddate><creator>Laurie, Lindsay E</creator><creator>Kokubo, Hiroki</creator><creator>Nakamura, Masataka</creator><creator>Saga, Yumiko</creator><creator>Funato, Noriko</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160226</creationdate><title>The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification</title><author>Laurie, Lindsay E ; Kokubo, Hiroki ; Nakamura, Masataka ; Saga, Yumiko ; Funato, Noriko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-e771277d569d71b46708fdf10b8729ceb1e3ac34bcec02aacd13c04f2ddcdbad3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Basic Helix-Loop-Helix Transcription Factors - physiology</topic><topic>Biocompatibility</topic><topic>Biology and Life Sciences</topic><topic>Biomedical materials</topic><topic>Bone and Bones - embryology</topic><topic>Bone and Bones - metabolism</topic><topic>Bone and Bones - pathology</topic><topic>Bones</topic><topic>Cartilage</topic><topic>Cbfa-1 protein</topic><topic>Cell Line</topic><topic>Chondrocytes</topic><topic>Chondrogenesis</topic><topic>Core Binding Factor Alpha 1 Subunit - antagonists & inhibitors</topic><topic>Core Binding Factor Alpha 1 Subunit - physiology</topic><topic>Deoxyribonucleic acid</topic><topic>Diaphyses</topic><topic>Diaphysis</topic><topic>Differentiation</topic><topic>DNA</topic><topic>Down-Regulation</topic><topic>Endochondral bone</topic><topic>Endochondral ossification</topic><topic>Epiphysis</topic><topic>Female</topic><topic>Femur</topic><topic>Gene expression</topic><topic>Genes, Reporter</topic><topic>Genetic aspects</topic><topic>Growth Plate - metabolism</topic><topic>Hedgehog protein</topic><topic>Hedgehog Proteins - biosynthesis</topic><topic>Hedgehog Proteins - deficiency</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - physiology</topic><topic>Helix-loop-helix proteins</topic><topic>Helix-loop-helix proteins (basic)</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Limb Deformities, Congenital - genetics</topic><topic>Long bone</topic><topic>Male</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mimicry</topic><topic>Ossification</topic><topic>Osteoblastogenesis</topic><topic>Osteogenesis</topic><topic>Osteogenesis - genetics</topic><topic>Osteogenesis - physiology</topic><topic>Osteopontin - biosynthesis</topic><topic>Osteopontin - genetics</topic><topic>Osteoprogenitor cells</topic><topic>Phenotype</topic><topic>Physiological aspects</topic><topic>Primordia</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Recombinant Fusion Proteins - 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Indian hedgehog (Ihh), a member of the hedgehog family of secreted molecules, regulates chondrocyte proliferation and differentiation, as well as osteoblast differentiation, through the process of endochondral ossification. Here, we report that the basic helix-loop-helix transcription factor Hand1, which is expressed in the cartilage primordia, is involved in proper osteogenesis of the bone collar via its control of Ihh production. Genetic overexpression of Hand1 in the osteochondral progenitors resulted in prenatal hypoplastic or aplastic ossification in the diaphyses, mimicking an Ihh loss-of-function phenotype. Ihh expression was downregulated in femur epiphyses of Hand1-overexpressing mice. We also confirmed that Hand1 downregulated Ihh gene expression in vitro by inhibiting Runx2 transactivation of the Ihh proximal promoter. These results demonstrate that Hand1 in chondrocytes regulates endochondral ossification, at least in part through the Runx2-Ihh axis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26918743</pmid><doi>10.1371/journal.pone.0150263</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Basic Helix-Loop-Helix Transcription Factors - genetics Basic Helix-Loop-Helix Transcription Factors - physiology Biocompatibility Biology and Life Sciences Biomedical materials Bone and Bones - embryology Bone and Bones - metabolism Bone and Bones - pathology Bones Cartilage Cbfa-1 protein Cell Line Chondrocytes Chondrogenesis Core Binding Factor Alpha 1 Subunit - antagonists & inhibitors Core Binding Factor Alpha 1 Subunit - physiology Deoxyribonucleic acid Diaphyses Diaphysis Differentiation DNA Down-Regulation Endochondral bone Endochondral ossification Epiphysis Female Femur Gene expression Genes, Reporter Genetic aspects Growth Plate - metabolism Hedgehog protein Hedgehog Proteins - biosynthesis Hedgehog Proteins - deficiency Hedgehog Proteins - genetics Hedgehog Proteins - physiology Helix-loop-helix proteins Helix-loop-helix proteins (basic) Kinases Laboratory animals Limb Deformities, Congenital - genetics Long bone Male Medicine and Health Sciences Mice Mice, Transgenic Mimicry Ossification Osteoblastogenesis Osteogenesis Osteogenesis - genetics Osteogenesis - physiology Osteopontin - biosynthesis Osteopontin - genetics Osteoprogenitor cells Phenotype Physiological aspects Primordia Promoter Regions, Genetic - genetics Real-Time Polymerase Chain Reaction Recombinant Fusion Proteins - metabolism Repressor Proteins - genetics Rodents Signal Transduction - physiology Transcription factors Transcriptional Activation Transfection Twist-Related Protein 1 - genetics |
| title | The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-13T15%3A07%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Transcription%20Factor%20Hand1%20Is%20Involved%20In%20Runx2-Ihh-Regulated%20Endochondral%20Ossification&rft.jtitle=PloS%20one&rft.au=Laurie,%20Lindsay%20E&rft.date=2016-02-26&rft.volume=11&rft.issue=2&rft.spage=e0150263&rft.epage=e0150263&rft.pages=e0150263-e0150263&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0150263&rft_dat=%3Cgale_plos_%3EA444363780%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1771271636&rft_id=info:pmid/26918743&rft_galeid=A444363780&rft_doaj_id=oai_doaj_org_article_cb0fe96fe515425ca6f444c8f58bbbf4&rfr_iscdi=true |