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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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Generation and skeletal analysis of Col1a1-Sox8 transgenic mice. (A) Schematic presentation of the DNA construct used for microinjection. Transgenic mice contain the Sox8-encoding ORF under the control of an osteoblast-specific Col1a1 promoter fragment. The location of the primers used for the transgene-specific expression analysis is indicated in red. (B) Analysis of transgene expression. RT-PCR expression analysis using transgene-specific primers reveals expression in bone and calvaria, as well as in primary osteoblasts at all stages of differentiation. (C) Staining of skeletons from newborn wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice with alcian blue and alizarin red. Skeletal elements of transgenic mice are reduced in size and staining intensity (arrows). Additionally, their clavicles and calvariae are hypomineralized (arrowheads).
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fig5: Generation and skeletal analysis of Col1a1-Sox8 transgenic mice. (A) Schematic presentation of the DNA construct used for microinjection. Transgenic mice contain the Sox8-encoding ORF under the control of an osteoblast-specific Col1a1 promoter fragment. The location of the primers used for the transgene-specific expression analysis is indicated in red. (B) Analysis of transgene expression. RT-PCR expression analysis using transgene-specific primers reveals expression in bone and calvaria, as well as in primary osteoblasts at all stages of differentiation. (C) Staining of skeletons from newborn wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice with alcian blue and alizarin red. Skeletal elements of transgenic mice are reduced in size and staining intensity (arrows). Additionally, their clavicles and calvariae are hypomineralized (arrowheads).

Mentions: The fact that Sox8 expression is down-regulated upon differentiation of wild-type osteoblasts raised the hypothesis that this down-regulation is a prerequisite for osteoblast differentiation. To interfere with Sox8 down-regulation in osteoblasts we generated transgenic mice that express Sox8 under the control of an osteoblast-specific Col1a1 promoter fragment that is active in osteoblast precursor cells and maintains its activity in differentiated osteoblasts (Rossert et al., 1995, 1996). The transgene consisted of the complete Sox8 ORF placed under the control of the 2.3-kb osteoblast-specific Col1a1 promoter fragment (Fig. 5 A). Four transgenic founders with similar phenotype and transgene expression were obtained. Three of them were used to generate transgenic mouse lines (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200408013/DC1). The fourth had to be killed at 10 d old because of spontaneous fracture. Expression analysis of the transgene using RT-PCR confirmed its bone-specific expression, as well as the expected lack of down-regulation during osteoblast differentiation (Fig. 5 B).


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)

Generation and skeletal analysis of Col1a1-Sox8 transgenic mice. (A) Schematic presentation of the DNA construct used for microinjection. Transgenic mice contain the Sox8-encoding ORF under the control of an osteoblast-specific Col1a1 promoter fragment. The location of the primers used for the transgene-specific expression analysis is indicated in red. (B) Analysis of transgene expression. RT-PCR expression analysis using transgene-specific primers reveals expression in bone and calvaria, as well as in primary osteoblasts at all stages of differentiation. (C) Staining of skeletons from newborn wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice with alcian blue and alizarin red. Skeletal elements of transgenic mice are reduced in size and staining intensity (arrows). Additionally, their clavicles and calvariae are hypomineralized (arrowheads).
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fig5: Generation and skeletal analysis of Col1a1-Sox8 transgenic mice. (A) Schematic presentation of the DNA construct used for microinjection. Transgenic mice contain the Sox8-encoding ORF under the control of an osteoblast-specific Col1a1 promoter fragment. The location of the primers used for the transgene-specific expression analysis is indicated in red. (B) Analysis of transgene expression. RT-PCR expression analysis using transgene-specific primers reveals expression in bone and calvaria, as well as in primary osteoblasts at all stages of differentiation. (C) Staining of skeletons from newborn wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice with alcian blue and alizarin red. Skeletal elements of transgenic mice are reduced in size and staining intensity (arrows). Additionally, their clavicles and calvariae are hypomineralized (arrowheads).
Mentions: The fact that Sox8 expression is down-regulated upon differentiation of wild-type osteoblasts raised the hypothesis that this down-regulation is a prerequisite for osteoblast differentiation. To interfere with Sox8 down-regulation in osteoblasts we generated transgenic mice that express Sox8 under the control of an osteoblast-specific Col1a1 promoter fragment that is active in osteoblast precursor cells and maintains its activity in differentiated osteoblasts (Rossert et al., 1995, 1996). The transgene consisted of the complete Sox8 ORF placed under the control of the 2.3-kb osteoblast-specific Col1a1 promoter fragment (Fig. 5 A). Four transgenic founders with similar phenotype and transgene expression were obtained. Three of them were used to generate transgenic mouse lines (Fig. S2, available at http://www.jcb.org/cgi/content/full/jcb.200408013/DC1). The fourth had to be killed at 10 d old because of spontaneous fracture. Expression analysis of the transgene using RT-PCR confirmed its bone-specific expression, as well as the expected lack of down-regulation during osteoblast differentiation (Fig. 5 B).

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