Cleidocranial Dysplasia in Mice

Mundlos, S; Huang, Lih-Fen; Selby, Paul B.; Olsen, Bjørn R.

doi:10.1111/j.1749-6632.1996.tb56290.x

Cited by 22 publications

(10 citation statements)

References 3 publications

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“…In humans, Cbfa1 shows haploinsufficiency, as mutation of one allele has been found in patients affected with the skeletal disorder cleidocranial dysplasia (26,31). A similar phenotype is observed in mice having a mutation in one allele of the gene (30,34). Mice deficient for Cbfa1/Runx2 develop a cartilaginous skeleton (24,34).…”

mentioning

confidence: 63%

High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

Geoffroy

Kneissel

Fournier

et al. 2002

Molecular and Cellular Biology

245

237

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The runt family transcription factor core-binding factor ␣1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-B ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.

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confidence: 63%

High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

Geoffroy

Kneissel

Fournier

et al. 2002

Molecular and Cellular Biology

245

237

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“…Previously, a ␥ radiation-induced mouse mutant, which showed a phenotype similar to that of CCD, was described (21). This mouse Ccd mutation was mapped to a region distal to that of H2 of chromosome 17 (22), where we previously mapped mouse homologue RUNX2 (8), and was found to result in a deletion of one of the alleles of Runx2 (17). Recently, RUNX2 was found to be heterozygously mutated in several CCD patients (18,23).…”

mentioning

confidence: 97%

A RUNX2/PEBP2 αA/ CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Zhang

Yasui

Ito

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

317

298

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Cleidocranial dysplasia (CCD), an autosomal-dominant human bone disease, is thought to be caused by heterozygous mutations in runt-related gene 2 (RUNX2)͞polyomavirus enhancer binding protein 2␣A (PEBP2␣A)͞core-binding factor A1 (CBFA1). To understand the mechanism underlying the pathogenesis of CCD, we studied a novel mutant of RUNX2, CCD␣A376, originally identified in a CCD patient. The nonsense mutation, which resulted in a truncated RUNX2 protein, severely impaired RUNX2 transactivation activity. We show that signal transducers of transforming growth factor ␤ superfamily receptors, Smads, interact with RUNX2 in vivo and in vitro and enhance the transactivation ability of this factor. The truncated RUNX2 protein failed to interact with and respond to Smads and was unable to induce the osteoblast-like phenotype in C2C12 myoblasts on stimulation by bone morphogenetic protein. Therefore, the pathogenesis of CCD may be related to the impaired Smad signaling of transforming growth factor ␤͞bone morphogenetic protein pathways that target the activity of RUNX2 during bone formation.

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“…While these extracellular matrix components do not directly regulate chondrocyte behavior, disturbances nevertheless have profound effects on the structural integrity of cartilage (Aszodi et al, 1998;Garofalo et al, 1993;Kwan et al, 1997;Li et al, 1995a;Mundlos et al, 1996;Wai et al, 1998;Watanabe and Yamada, 1999;Yang et al, 1997). Indeed, collagen gene mutations feature prominently as causes for human chondrodysplasias (Francomano et al, 1996;Mundlos and Olsen, 1997b).…”

Section: Local Control Of Bone Shape During Embryogenesis and Growthmentioning

confidence: 99%

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

Kappen

Neubüser

Balling

et al. 2007

Birth Defects Research Pt B

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Skeletal variations are common in humans, and potentially are caused by genetic as well as environmental factors. We here review molecular principles in skeletal development to develop a knowledge base of possible alterations that could explain variations in skeletal element number, shape or size. Environmental agents that induce variations, such as teratogens, likely interact with the molecular pathways that regulate skeletal development. Birth Defects Res (Part B), 80:425–450, 2007. © 2007 Wiley‐Liss, Inc.

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Cleidocranial Dysplasia in Mice

Cited by 22 publications

References 3 publications

High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

A RUNX2/PEBP2 αA/ CBFA1 mutation displaying impaired transactivation and Smad interaction in cleidocranial dysplasia

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

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