Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of <i>Indian hedgehog</i>

Yoshida, Chisato; Yamamoto, Hiromitsu; Fujita, Takashi; Furuichi, Tatsuya; Ito, Kosei; Inoue, Ken; Yamana, Kei; Zanma, Akira; Takada, Kenji; Ito, Yoshiaki; Komori, Toshihisa

doi:10.1101/gad.1174704

Cited by 528 publications

(568 citation statements)

References 34 publications

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“…Runx2 is normally expressed in proliferating and hypertrophic chondrocytes in the growth plate, with highest expression in terminal hypertrophic chondrocytes. 5 Runx2 induces genes typical of terminal chondrocyte differentiation, including type X collagen, MMP-13, and Ihh, 5,29,30 thus it is not surprising that these genes are also up-regulated in OC lesions (as demonstrated here for MMP-13, and by Semevolos et al, 2005 11 for Ihh).…”

Section: Discussionmentioning

confidence: 59%

Altered gene expression in early osteochondrosis lesions

Mirams

Tatarczuch

Ahmed

et al. 2009

Journal Orthopaedic Research

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Osteochondrosis is a condition involving defective endochondral ossification and retention of cartilage in subchondral bone. The pathophysiology of this condition is poorly characterized, but it has been proposed that the fundamental defect is failure of chondrocyte hypertrophy. The aim of the current study was to characterize phenotypic changes in chondrocytes associated with the initiation of osteochondrosis. Early lesions were induced in an equine model of osteochondrosis by feeding foals a high energy diet for 8 or 15 weeks. Lesions in articular-epiphyseal growth cartilage were examined histologically and by quantitative PCR analysis of expression of a number of genes representative of pathways that regulate chondrocyte behavior during endochondral ossification. There were more cells present in clusters in the lesions compared to normal articular cartilage. Expression of matrix metalloproteinase-13, type I collagen, type X collagen, and Runx2 mRNA was significantly greater in the lesions compared to normal cartilage from the same joint. Expression of vascular endothelial growth factor, type II collagen, connective tissue growth factor, aggrecan, Sox9, and fibroblast growth factor receptor 3 mRNA was not significantly different in lesions than in control cartilage. These observations suggest that osteochondrosis does not result from failure of chondrocytes to undergo hypertrophy. During the process of endochondral ossification, chondrocytes in growth cartilage undergo proliferation, followed by hypertrophy and physiological death. This orderly series of events is regulated by a number of secreted proteins, the actions of which are mediated by specific receptors, signaling cascades, and transcription factors. 1 Several factors are of particular interest. The high-mobility-group transcription factor Sox9 is the earliest known determinant of chondrocyte differentiation and cartilage formation, also regulating expression of the chondrocyte-specific extracellular matrix proteins type II collagen and aggrecan. 2 Fibroblast growth factor receptor 3 (FGFR3) has been shown to inhibit chondrocyte proliferation, with FGF18 possibly the important ligand in growth cartilage. 3,4 Endochondral ossification is blocked in Runx2-deficient mice, indicating an essential role for this transcription factor in chondrocyte differentiation. It has been shown that expression of Runx2 induces hypertrophy, alkaline phosphatase activity, and expression of type X collagen and matrix metalloproteinase-13 (MMP-13) 5 in chondrocytes, as well as mineralization of the cartilage matrix. In the later stages of endochondral ossification, Runx2 is involved in the vascular invasion of the cartilage, inducing the expression of the angiogenic factor, vascular endothelial growth factor (VEGF), which is necessary for vascular invasion, as well as the expression of VEGF receptors. 6 Evidence from a mouse model has shown that the collagen-degrading enzyme MMP-13 plays a role in invasion of the ossification front, with delayed endochondral ossif...

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Section: Discussionmentioning

confidence: 59%

Altered gene expression in early osteochondrosis lesions

Mirams

Tatarczuch

Ahmed

et al. 2009

Journal Orthopaedic Research

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“…Hand2 levels in the limb may modulate the availability of Twist1 for interaction with Runx proteins. Or, as Runx mutants with polydactyly have not been described [35][36][37][38] , interactions between Hand2 and Twist1 in the early limb may operate independently of Runx pathways. Whether changes in Hand2 gene dosage can alter osteogenic SCS phenotypes is an interesting question.…”

Section: Discussionmentioning

confidence: 99%

Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities

et al. 2005

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Autosomal dominant mutations in the bHLH transcription factor TWIST1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome (SCS). The molecular mechanism underlying these phenotypes is poorly understood. We show that the ectopic expression of the related bHLH factor Hand2 phenocopies Twist1 loss-of-function phenotypes in the limb, and that they display a gene dosage-dependent antagonistic interaction. Twist1 and Hand2 dimerization partner choice can be modulated by PKA and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues. Interestingly, multiple TWIST1 mutations associated with SCS alter PKA-mediated Twist1 phosphorylation, suggesting that misregulation of Twist1 dimerization via either stoichiometric or posttranslational mechanisms underlies SCS phenotypes.Studies of developing vertebrate limbs have yielded many insights into the process of embryonic pattern formation. Prominent among these are the identification of a growing catalog of transcription factors that orchestrate limb patterning. While the genetic and biochemical interactions of these transcription factors are clearly important for integrating patterning information, these interactions are poorly understood. Twist1 and Hand2 are basic helix-loop-helix (bHLH) transcription factors within the Twist family, and are attractive candidates for investigating such interactions. Each is required for distinct yet subtly related aspects of limb development, and biochemical studies have revealed a complex regulation of their protein-protein interactions 1-3 .Early limb bud expression of Twist1 is observed primarily in the peripheral mesenchyme, and Twist1 is required for maintenance of the overlying apical ectodermal ridge (AER) 4-7 . Twist1 haploinsufficiency in mice and humans is associated with a range of limb abnormalities. Twist1 heterozygous null mice display a partially penetrant preaxial polydactyly 8,9 . Human Correspondence should be addressed to A.B.F. tfirulli@iupui.edu (317) 278-5814 and E.L. elaufer@columbia.edu (212) Here we investigate the biochemical and genetic interactions between Twist1 and Hand2 both in vitro and during limb development. We show that PKA and B56δ-containing PP2A can regulate Twist1 and Hand2 phosphorylation at the conserved helix I residues, that hypophosphorylation and phosphorylation mimics of these residues alter bHLH dimerization affinities, and that a population of TWIST1 mutations that cause SCS in humans exhibit disregulation of this phosphoregulatory circuit. We also show that ectopic Hand2 expression phenocopies multiple SCS-like limb phenotypes, that the appropriate genetic dosage of Hand2 and Twist1 is critical for proper limb development, and that these interactions require the phosphoregulated helix I residues. These findings support a mechanism where the Twist family dimerization partner choices are modulated by both the relative levels of gene expression and the phosphorylation state of key helix I residues, thereby dictating changes i...

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“…Transgenic mice deficient of Runx2 (Runx2 À/À ) lacked mineralized bone matrix and chondrocytes were unable to undergo hypertrophic differentiation, as indicated by the absence of Ihh and collagen type X, suggesting that Runx2 was required for both chondrocyte and osteoblast differentiation [Kim et al, 1999]. A recent study focused on regulation of Ihh demonstrated that Runx2 can directly induce Ihh transcription [Yoshida et al, 2004]. They showed that Runx2 À/À mice had dramatically reduced Ihh expression that could be restored by overexpression of Runx2.…”

Section: Stimulators Of Ihh Expressionmentioning

confidence: 99%

Indian hedgehog: Its roles and regulation in endochondral bone development

Lai

Mitchell

2005

J of Cellular Biochemistry

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Normal endochondral bone development requires the coordination of chondrocyte proliferation and differentiation. Indian hedgehog (Ihh) is a morphogen produced by chondrocytes in the early stage of terminal differentiation and plays several key roles in this process. Ihh regulates growth of adjacent proliferative chondrocytes and can also regulate the rate of differentiation of chondrocytes indirectly through its stimulation of parathyroid hormonerelated protein (PTHrP). In this review, we focus on recent studies that have identified new functions of Ihh and how Ihh itself is being regulated.

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Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog

Cited by 528 publications

References 34 publications

Altered gene expression in early osteochondrosis lesions

Altered gene expression in early osteochondrosis lesions

Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities

Indian hedgehog: Its roles and regulation in endochondral bone development

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