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The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation.

Schmidt K, Schinke T, Haberland M, Priemel M, Schilling AF, Mueldner C, Rueger JM, Sock E, Wegner M, Amling M - J. Cell Biol. (2005)

Bottom Line: This is achieved through a balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts.In this study, we identify the high mobility group transcription factor Sox8 as a physiologic regulator of bone formation.Together, these data demonstrate a novel function of Sox8, whose tightly controlled expression is critical for bone formation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Friedrich-Alexander-University, Erlangen-Nürnberg, Erlangen 91054, Germany.

ABSTRACT
Bone remodeling is an important physiologic process that is required to maintain a constant bone mass. This is achieved through a balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we identify the high mobility group transcription factor Sox8 as a physiologic regulator of bone formation. Sox8-deficient mice display a low bone mass phenotype that is caused by a precocious osteoblast differentiation. Accordingly, primary osteoblasts derived from these mice show an accelerated mineralization ex vivo and a premature expression of osteoblast differentiation markers. To confirm the function of Sox8 as a negative regulator of osteoblast differentiation we generated transgenic mice that express Sox8 under the control of an osteoblast-specific Col1a1 promoter fragment. These mice display a severely impaired bone formation that can be explained by a strongly reduced expression of runt-related transcription factor 2, a gene encoding a transcription factor required for osteoblast differentiation. Together, these data demonstrate a novel function of Sox8, whose tightly controlled expression is critical for bone formation.

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Bone phenotype of Col1a1-Sox8 transgenic mice. (A) Radiographic analysis of skeletons from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old. Transgenic mice are smaller, display increased radiolucency compared with wild-type littermates (arrows) and have hypoplastic clavicles (arrowheads). (B) μCT imaging reveals that the Col1a1-Sox8 transgenic mice have severe defects in calvarial bone formation and fontanelle closure. (C) Histological analysis of vertebral bodies from wild-type and transgenic mice at 2 wk (top) and 10 wk (bottom) old. Von Kossa staining of undecalcified sections reveals a low bone mass phenotype in Col1a1-Sox8 transgenic mice. Histomorphometric quantification shows that the trabecular bone volume (BV/TV) is significantly reduced in transgenic mice at both ages. Values represent means ± SEM. Asterisks indicate statistically significant differences between the two groups (n = 5). **, P < 0.005.
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fig6: Bone phenotype of Col1a1-Sox8 transgenic mice. (A) Radiographic analysis of skeletons from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old. Transgenic mice are smaller, display increased radiolucency compared with wild-type littermates (arrows) and have hypoplastic clavicles (arrowheads). (B) μCT imaging reveals that the Col1a1-Sox8 transgenic mice have severe defects in calvarial bone formation and fontanelle closure. (C) Histological analysis of vertebral bodies from wild-type and transgenic mice at 2 wk (top) and 10 wk (bottom) old. Von Kossa staining of undecalcified sections reveals a low bone mass phenotype in Col1a1-Sox8 transgenic mice. Histomorphometric quantification shows that the trabecular bone volume (BV/TV) is significantly reduced in transgenic mice at both ages. Values represent means ± SEM. Asterisks indicate statistically significant differences between the two groups (n = 5). **, P < 0.005.

Mentions: Because this phenotype did not lead to postnatal lethality, we next analyzed wild-type and transgenic mice at 2 wk old. Using contact radiography we observed an increased radiolucency in transgenic mice demonstrating a low bone mass phenotype (Fig. 6 A). Additionally, we found a size reduction of all skeletal elements compared with wild-type littermates, including the clavicles. The severe hypomineralization of calvariae that was still prominent in the transgenic mice at 2 wk old was further visualized by μCT imaging (Fig. 6 B). Histomorphometric analysis of vertebral sections demonstrated that the trabecular bone volume in transgenic mice was reduced by 40% at 2 wk old and by 30% at 10 wk old compared with wild-type littermates (Fig. 6 C).


The high mobility group transcription factor Sox8 is a negative regulator of osteoblast differentiation.

Schmidt K, Schinke T, Haberland M, Priemel M, Schilling AF, Mueldner C, Rueger JM, Sock E, Wegner M, Amling M - J. Cell Biol. (2005)

Bone phenotype of Col1a1-Sox8 transgenic mice. (A) Radiographic analysis of skeletons from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old. Transgenic mice are smaller, display increased radiolucency compared with wild-type littermates (arrows) and have hypoplastic clavicles (arrowheads). (B) μCT imaging reveals that the Col1a1-Sox8 transgenic mice have severe defects in calvarial bone formation and fontanelle closure. (C) Histological analysis of vertebral bodies from wild-type and transgenic mice at 2 wk (top) and 10 wk (bottom) old. Von Kossa staining of undecalcified sections reveals a low bone mass phenotype in Col1a1-Sox8 transgenic mice. Histomorphometric quantification shows that the trabecular bone volume (BV/TV) is significantly reduced in transgenic mice at both ages. Values represent means ± SEM. Asterisks indicate statistically significant differences between the two groups (n = 5). **, P < 0.005.
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Related In: Results  -  Collection

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fig6: Bone phenotype of Col1a1-Sox8 transgenic mice. (A) Radiographic analysis of skeletons from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old. Transgenic mice are smaller, display increased radiolucency compared with wild-type littermates (arrows) and have hypoplastic clavicles (arrowheads). (B) μCT imaging reveals that the Col1a1-Sox8 transgenic mice have severe defects in calvarial bone formation and fontanelle closure. (C) Histological analysis of vertebral bodies from wild-type and transgenic mice at 2 wk (top) and 10 wk (bottom) old. Von Kossa staining of undecalcified sections reveals a low bone mass phenotype in Col1a1-Sox8 transgenic mice. Histomorphometric quantification shows that the trabecular bone volume (BV/TV) is significantly reduced in transgenic mice at both ages. Values represent means ± SEM. Asterisks indicate statistically significant differences between the two groups (n = 5). **, P < 0.005.
Mentions: Because this phenotype did not lead to postnatal lethality, we next analyzed wild-type and transgenic mice at 2 wk old. Using contact radiography we observed an increased radiolucency in transgenic mice demonstrating a low bone mass phenotype (Fig. 6 A). Additionally, we found a size reduction of all skeletal elements compared with wild-type littermates, including the clavicles. The severe hypomineralization of calvariae that was still prominent in the transgenic mice at 2 wk old was further visualized by μCT imaging (Fig. 6 B). Histomorphometric analysis of vertebral sections demonstrated that the trabecular bone volume in transgenic mice was reduced by 40% at 2 wk old and by 30% at 10 wk old compared with wild-type littermates (Fig. 6 C).

Bottom Line: This is achieved through a balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts.In this study, we identify the high mobility group transcription factor Sox8 as a physiologic regulator of bone formation.Together, these data demonstrate a novel function of Sox8, whose tightly controlled expression is critical for bone formation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Friedrich-Alexander-University, Erlangen-Nürnberg, Erlangen 91054, Germany.

ABSTRACT
Bone remodeling is an important physiologic process that is required to maintain a constant bone mass. This is achieved through a balanced activity of bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we identify the high mobility group transcription factor Sox8 as a physiologic regulator of bone formation. Sox8-deficient mice display a low bone mass phenotype that is caused by a precocious osteoblast differentiation. Accordingly, primary osteoblasts derived from these mice show an accelerated mineralization ex vivo and a premature expression of osteoblast differentiation markers. To confirm the function of Sox8 as a negative regulator of osteoblast differentiation we generated transgenic mice that express Sox8 under the control of an osteoblast-specific Col1a1 promoter fragment. These mice display a severely impaired bone formation that can be explained by a strongly reduced expression of runt-related transcription factor 2, a gene encoding a transcription factor required for osteoblast differentiation. Together, these data demonstrate a novel function of Sox8, whose tightly controlled expression is critical for bone formation.

Show MeSH
Related in: MedlinePlus