Msx2 −/− transgenic mice develop compound amelogenesis imperfecta, dentinogenesis imperfecta and periodental osteopetrosis

Aïoub, Muhanad; Lezot, Frédéric; Molla, Muriel; Castañeda, Beatriz; Robert, Benoît; Goubin, Gérard; Nefussi, Jean-Raphaël; Berdal, Ariane

doi:10.1016/j.bone.2007.07.023

Cited by 76 publications

(135 citation statements)

References 41 publications

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“…3,6 These studies demonstrated additional roles for MSX2 in physiological regulation of postnatal mineralized tissue formation, modeling and homeostasis. In addition to enamel and dentin dysplasia and altered root formation, these mutant mice exhibit regional osteopetrosis resulting from site-specific down-regulation of RANKL expression in the alveolar bone 6 which mechanisms are not understood. In addition to osteocalcin and amelogenin, other enamel matrix proteins constitute candidate MSX2 targets.…”

Section: Msx2mentioning

confidence: 88%

“…These-ones include: cranial suture closing, epithelial-mesenchymal interactions leading to crown morphogenesis, 5 and ameloblast cell differentiation. 6,7 A gain-of-function mutation in the Msx2 homeobox-gene sequence induces premature suture fusion (Boston-type 2 craniosynostosis; OMIM 604757). 8 Conversely, a mutation leading to reduced MSX2 DNA-binding is associated with impaired suture closing in the parietal foramina (OMIM 168500).…”

Section: Msx2mentioning

confidence: 99%

“…10 Different mouse models (null mutant mice, 5 transgenic mice bearing overexpression constructs 11 and gene mutations 12,13 ) mimic the multiple craniofacial anomalies: precocious fusion of cranial bones, development of ectopic cranial bone, 12 or contrarily, persistent calvaria foramina and dental defects, 5 and reduction of bone ossification 13 and resorption. 6 The present investigation focuses on the physiopathology of enamel and periodontal tissues in a knockin transgenic mouse model. MSX2 was shown to be mediated through interactions with distinct transcriptional factors such as DLX homeoproteins for osteocalcin 15 and the CCAAT/enhancerbinding protein ␣ (C/EBP␣) for amelogenin.…”

Section: Msx2mentioning

confidence: 99%

“…6 Heterozygous males and females were mated using a CD1 Swiss genetic background. Their litters were used to compare wild-type (Msx2 …”

Section: Expression Analysis In Knockin Msx2/lacz Transgenic Micementioning

confidence: 99%

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Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice

Molla

Descroix

Aïoub

et al. 2010

The American Journal of Pathology

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Signaling pathways that underlie postnatal dental and periodontal physiopathology are less studied than those of early tooth development. Members of the muscle segment homeobox gene (Msx) family encode homeoproteins that show functional redundancy during development and are known to be involved in epithelial-mesenchymal interactions that lead to crown morphogenesis and ameloblast cell differentiation. This study analyzed the MSX2 protein during mouse postnatal growth as well as in the adult. The analysis focused on enamel and periodontal defects and enamel proteins in Msx2-null mutant mice. In the epithelial lifecycle, the levels of MSX2 expression and enamel protein secretion were inversely related. Msx2؉/؊ mice showed increased amelogenin expression, enamel thickness, and rod size. Msx2 ؊/؊ mice displayed compound phenotypic characteristics of enamel defects, related to both enamel-specific gene mutations (amelogenin and enamelin) in isolated amelogenesis imperfecta, and cell-cell junction elements (laminin 5 and cytokeratin 5) in other syndromes. These effects were also related to ameloblast disappearance, which differed between incisors and molars. In Msx2 ؊/؊ roots, Malassez cells formed giant islands that overexpressed amelogenin and ameloblastin that grew over months. Aberrant expression of enamel proteins is proposed to underlie the regional osteopetrosis and hyperproduction of cellular cementum. These enamel and periodontal phenotypes of Msx2 mutants constitute the first case report of structural and signaling defects associated with enamel protein overexpression in a postnatal context.

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Section: Msx2mentioning

confidence: 88%

Section: Msx2mentioning

confidence: 99%

Section: Msx2mentioning

confidence: 99%

“…6 Heterozygous males and females were mated using a CD1 Swiss genetic background. Their litters were used to compare wild-type (Msx2 …”

Section: Expression Analysis In Knockin Msx2/lacz Transgenic Micementioning

confidence: 99%

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Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice

Molla

Descroix

Aïoub

et al. 2010

The American Journal of Pathology

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“…A TRAP activity assay was performed as previously described. 46 For detailed quantification methods, see Supplementary information.…”

Section: Dlx5/dlx6mentioning

confidence: 99%

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Isaac

Gordon

et al. 2014

Cell Death Differ

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Human mutations and in vitro studies indicate that DLX3 has a crucial function in bone development, however, the in vivo role of DLX3 in endochondral ossification has not been established. Here, we identify DLX3 as a central attenuator of adult bone mass in the appendicular skeleton. Dynamic bone formation, histologic and micro-computed tomography analyses demonstrate that in vivo DLX3 conditional loss of function in mesenchymal cells (Prx1-Cre) and osteoblasts (OCN-Cre) results in increased bone mass accrual observed as early as 2 weeks that remains elevated throughout the lifespan owing to increased osteoblast activity and increased expression of bone matrix genes. Dlx3OCN-conditional knockout mice have more trabeculae that extend deeper in the medullary cavity and thicker cortical bone with an increased mineral apposition rate, decreased bone mineral density and increased cortical porosity. Trabecular TRAP staining and site-specific Q-PCR demonstrated that osteoclastic resorption remained normal on trabecular bone, whereas cortical bone exhibited altered osteoclast patterning on the periosteal surface associated with high Opg/Rankl ratios. Using RNA sequencing and chromatin immunoprecipitation-Seq analyses, we demonstrate that DLX3 regulates transcription factors crucial for bone formation such as Dlx5, Dlx6, Runx2 and Sp7 as well as genes important to mineral deposition (Ibsp, Enpp1, Mepe) and bone turnover (Opg). Furthermore, with the removal of DLX3, we observe increased occupancy of DLX5, as well as increased and earlier occupancy of RUNX2 on the bone-specific osteocalcin promoter. Together, these findings provide novel insight into mechanisms by which DLX3 attenuates bone mass accrual to support bone homeostasis by osteogenic gene pathway regulation. Endochondral bone formation (EBF) and homeostasis require a regulated program of mesenchymal condensation, chondrocyte differentiation, vascular invasion, cartilage resorption, osteoprogenitor recruitment and differentiation and bone remodeling. These key processes are under the control of essential bone transcription factors (TFs), including RUNX2, SP7 and homeodomain protein families such as HOX, MSX and DLX.1-3 DLX proteins are important regulators of developmental and differentiation processes, including skeletal development. [4][5][6] A missense mutation in DLX5 leads to split hand and foot malformation 7 and DLX5 and DLX6 are positive transcriptional regulators of osteochondroblastic differentiation. 6 DLX3 is defined as an osteogenic regulator, as human mutations in DLX3 lead to tricho-dento-osseous (TDO) syndrome, an ectodermal dysplasia that causes increased bone mineral density (BMD) in intramembranous and endochondral bones. In vitro, osteocalcin (Ocn), Runx2 9,10 and osteoactivin [9][10][11] are directly regulated by DLX3, and overexpression of DLX3 in osteoprogenitors stimulates transcription of osteogenic markers. 9Recently, we investigated the effects of neural crest deletion of Dlx3 in craniofacial bones. 12 The gene signature of craniofacial...

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Tooth Root Development

Foster

Nociti

Somerman

2013

Stem Cells in Craniofacial Development and Regeneration

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Msx2 −/− transgenic mice develop compound amelogenesis imperfecta, dentinogenesis imperfecta and periodental osteopetrosis

Cited by 76 publications

References 41 publications

Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice

Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice

DLX3 regulates bone mass by targeting genes supporting osteoblast differentiation and mineral homeostasis in vivo

Tooth Root Development

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