title: Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog.
abstract: The differentiation of mesenchymal cells into chondrocytes and chondrocyte proliferation and maturation are fundamental steps in skeletal development. Runx2 is essential for osteoblast differentiation and is involved in chondrocyte maturation. Although chondrocyte maturation is delayed in Runx2-deficient (Runx2(-/-)) mice, terminal differentiation of chondrocytes does occur, indicating that additional factors are involved in chondrocyte maturation. We investigated the involvement of Runx3 in chondrocyte differentiation by generating Runx2-and-Runx3-deficient (Runx2(-/-)3(-/-)) mice. We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2(-/-)3(-/-) mice showed a complete absence of chondrocyte maturation. Further, the length of the limbs was reduced depending on the dosages of Runx2 and Runx3, due to reduced and disorganized chondrocyte proliferation and reduced cell size in the diaphyses. Runx2(-/-)3(-/-) mice did not express Ihh, which regulates chondrocyte proliferation and maturation. Adenoviral introduction of Runx2 in Runx2(-/-) chondrocyte cultures strongly induced Ihh expression. Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter. These findings demonstrate that Runx2 and Runx3 are essential for chondrocyte maturation and that Runx2 regulates limb growth by organizing chondrocyte maturation and proliferation through the induction of Ihh expression.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Carolina A
authors.initials: CA
authors.lastname: Yoshida
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujita
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Kosei
authors.initials: K
authors.lastname: Ito
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Kei
authors.initials: K
authors.lastname: Yamana
authors.forename: Akira
authors.initials: A
authors.lastname: Zanma
authors.forename: Kenji
authors.initials: K
authors.lastname: Takada
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Komori
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D053823:Hedgehog Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; C493730:Runx3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors