title: The Transcription Factor Hand1 Is Involved In Runx2-Ihh-Regulated Endochondral Ossification.
abstract: 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.
authors.affiliation: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Laurie
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Mishima, Shizuoka, Japan.|Department of Genetics, The Graduate University for Advanced Studies, Mishima, Shizuoka, Japan.|Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Minamiku, Hiroshima, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kokubo
authors.affiliation: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Mishima, Shizuoka, Japan.|Department of Genetics, The Graduate University for Advanced Studies, Mishima, Shizuoka, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.affiliation: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Funato
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology; D018483:Diaphyses; D015536:Down-Regulation; D005260:Female; D017930:Genes, Reporter; D006132:Growth Plate / Q000378:metabolism; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017880:Limb Deformities, Congenital / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D053823:Hedgehog Proteins; D053495:Osteopontin; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; C095572:Hand1 protein, mouse; C493716:Runx2 protein, mouse; C506896:Spp1 protein, mouse; C096852:Twist2 protein, mouse; C514061:ihh protein, mouse