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Molecular study of a Hoxa2 gain-of-function in chondrogenesis: a model of idiopathic proportionate short stature.

Deprez PM, Nichane MG, Lengelé BG, Rezsöhazy R, Nyssen-Behets C - Int J Mol Sci (2013)

Bottom Line: Our analysis showed that this overall size reduction was correlated with a negative influence of Hoxa2 at the first step of endochondral ossification.These data confirm the impairment of chondrogenic differentiation by Hoxa2 overexpression.They also show a selective effect of Hoxa2 on endochondral ossification processes since Gdf5 and Gdf10, and Bmp4 or PthrP were up-regulated and unmodified, respectively.

View Article: PubMed Central - PubMed

Affiliation: Ecole de Kinésiologie et Récréologie, Faculté des Sciences de la Santé et Services Communautaires, Université de Moncton, Moncton, NB E1A 3E9, Canada. catherine.behets@uclouvain.be.

ABSTRACT
In a previous study using transgenic mice ectopically expressing Hoxa2 during chondrogenesis, we associated the animal phenotype to human idiopathic proportionate short stature. Our analysis showed that this overall size reduction was correlated with a negative influence of Hoxa2 at the first step of endochondral ossification. However, the molecular pathways leading to such phenotype are still unknown. Using protein immunodetection and histological techniques comparing transgenic mice to controls, we show here that the persistent expression of Hoxa2 in chondrogenic territories provokes a general down-regulation of the main factors controlling the differentiation cascade, such as Bapx1, Bmp7, Bmpr1a, Ihh, Msx1, Pax9, Sox6, Sox9 and Wnt5a. These data confirm the impairment of chondrogenic differentiation by Hoxa2 overexpression. They also show a selective effect of Hoxa2 on endochondral ossification processes since Gdf5 and Gdf10, and Bmp4 or PthrP were up-regulated and unmodified, respectively. Since Hoxa2 deregulation in mice induces a proportionate short stature phenotype mimicking human idiopathic conditions, our results give an insight into understanding proportionate short stature pathogenesis by highlighting molecular factors whose combined deregulation may be involved in such a disease.

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Model featuring the molecular deregulation induced by Hoxa2 over-expression and associated with a proposed mechanism leading to idiopathic proportionate short stature. Molecular expressions are featured with their function and interactions on the left panel according to the mesenchymal (Col1a1, upper quadrant), differentiating (Col2a1, middle quadrant) and hypertrophic (Col10a1, lower quadrant) stages. Molecules are presented with their known interactions according to the literature [11,15,17,18,28,29,31–40]. Molecules that present a negative or positive influence on differentiation are shown in red and green, respectively (left panel). The factors that were reduced or increased in their protein levels in Col2a1/Hoxa2-lacZ are featured with red or green arrows, respectively (right panel). The stars indicate a significant difference observed using western blotting semi-quantification.
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f2-ijms-14-20386: Model featuring the molecular deregulation induced by Hoxa2 over-expression and associated with a proposed mechanism leading to idiopathic proportionate short stature. Molecular expressions are featured with their function and interactions on the left panel according to the mesenchymal (Col1a1, upper quadrant), differentiating (Col2a1, middle quadrant) and hypertrophic (Col10a1, lower quadrant) stages. Molecules are presented with their known interactions according to the literature [11,15,17,18,28,29,31–40]. Molecules that present a negative or positive influence on differentiation are shown in red and green, respectively (left panel). The factors that were reduced or increased in their protein levels in Col2a1/Hoxa2-lacZ are featured with red or green arrows, respectively (right panel). The stars indicate a significant difference observed using western blotting semi-quantification.

Mentions: We showed that mice with an ectopic expression of Hoxa2 feature decreased Bapx1, Bmp7, Bmpr1a, Ihh, Msx1, Pax9, Sox6, Sox9 and Wnt5a and increased Gdf5 and Gdf10 protein levels. When significant, the protein level reductions reached up to one eighth of the control ones. The other molecules showed similar patterns for both immunohistochemistry and western blots (Figure 1). This is interesting since most of the decreased proteins stimulate the mesenchymal-to-chondrocyte transition [10,11,15,28–31] (Figure 2, left panel). This is consistent with the observation that continued Hoxa2 expression impairs the early differentiation of mesenchymal cells into chondrocytes [4].


Molecular study of a Hoxa2 gain-of-function in chondrogenesis: a model of idiopathic proportionate short stature.

Deprez PM, Nichane MG, Lengelé BG, Rezsöhazy R, Nyssen-Behets C - Int J Mol Sci (2013)

Model featuring the molecular deregulation induced by Hoxa2 over-expression and associated with a proposed mechanism leading to idiopathic proportionate short stature. Molecular expressions are featured with their function and interactions on the left panel according to the mesenchymal (Col1a1, upper quadrant), differentiating (Col2a1, middle quadrant) and hypertrophic (Col10a1, lower quadrant) stages. Molecules are presented with their known interactions according to the literature [11,15,17,18,28,29,31–40]. Molecules that present a negative or positive influence on differentiation are shown in red and green, respectively (left panel). The factors that were reduced or increased in their protein levels in Col2a1/Hoxa2-lacZ are featured with red or green arrows, respectively (right panel). The stars indicate a significant difference observed using western blotting semi-quantification.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821620&req=5

f2-ijms-14-20386: Model featuring the molecular deregulation induced by Hoxa2 over-expression and associated with a proposed mechanism leading to idiopathic proportionate short stature. Molecular expressions are featured with their function and interactions on the left panel according to the mesenchymal (Col1a1, upper quadrant), differentiating (Col2a1, middle quadrant) and hypertrophic (Col10a1, lower quadrant) stages. Molecules are presented with their known interactions according to the literature [11,15,17,18,28,29,31–40]. Molecules that present a negative or positive influence on differentiation are shown in red and green, respectively (left panel). The factors that were reduced or increased in their protein levels in Col2a1/Hoxa2-lacZ are featured with red or green arrows, respectively (right panel). The stars indicate a significant difference observed using western blotting semi-quantification.
Mentions: We showed that mice with an ectopic expression of Hoxa2 feature decreased Bapx1, Bmp7, Bmpr1a, Ihh, Msx1, Pax9, Sox6, Sox9 and Wnt5a and increased Gdf5 and Gdf10 protein levels. When significant, the protein level reductions reached up to one eighth of the control ones. The other molecules showed similar patterns for both immunohistochemistry and western blots (Figure 1). This is interesting since most of the decreased proteins stimulate the mesenchymal-to-chondrocyte transition [10,11,15,28–31] (Figure 2, left panel). This is consistent with the observation that continued Hoxa2 expression impairs the early differentiation of mesenchymal cells into chondrocytes [4].

Bottom Line: Our analysis showed that this overall size reduction was correlated with a negative influence of Hoxa2 at the first step of endochondral ossification.These data confirm the impairment of chondrogenic differentiation by Hoxa2 overexpression.They also show a selective effect of Hoxa2 on endochondral ossification processes since Gdf5 and Gdf10, and Bmp4 or PthrP were up-regulated and unmodified, respectively.

View Article: PubMed Central - PubMed

Affiliation: Ecole de Kinésiologie et Récréologie, Faculté des Sciences de la Santé et Services Communautaires, Université de Moncton, Moncton, NB E1A 3E9, Canada. catherine.behets@uclouvain.be.

ABSTRACT
In a previous study using transgenic mice ectopically expressing Hoxa2 during chondrogenesis, we associated the animal phenotype to human idiopathic proportionate short stature. Our analysis showed that this overall size reduction was correlated with a negative influence of Hoxa2 at the first step of endochondral ossification. However, the molecular pathways leading to such phenotype are still unknown. Using protein immunodetection and histological techniques comparing transgenic mice to controls, we show here that the persistent expression of Hoxa2 in chondrogenic territories provokes a general down-regulation of the main factors controlling the differentiation cascade, such as Bapx1, Bmp7, Bmpr1a, Ihh, Msx1, Pax9, Sox6, Sox9 and Wnt5a. These data confirm the impairment of chondrogenic differentiation by Hoxa2 overexpression. They also show a selective effect of Hoxa2 on endochondral ossification processes since Gdf5 and Gdf10, and Bmp4 or PthrP were up-regulated and unmodified, respectively. Since Hoxa2 deregulation in mice induces a proportionate short stature phenotype mimicking human idiopathic conditions, our results give an insight into understanding proportionate short stature pathogenesis by highlighting molecular factors whose combined deregulation may be involved in such a disease.

Show MeSH
Related in: MedlinePlus