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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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Analysis of endochondral and intramembranous ossification in Sox8-deficient mice. (A) Staining of wild-type (WT) and Sox8-deficient (−/−) skeletons with alcian blue and alizarin red at 17.5 dpc of embryonic development. No gross abnormalities were observed in the absence of Sox8. (B) Staining of undecalcified tibia sections with Toluidine blue and silver nitrate at 16.5 and 18.5 dpc, as well as in newborn wild-type and Sox8-deficient mice. No significant defects of endochondral ossification were observed in the absence of Sox8. (C) Radiographic analysis of skeletons from wild-type and Sox8-deficient mice at 6 wk old. The Sox8-deficient mice are smaller, show an increased radiolucency (arrows) and display hypoplastic clavicles (arrowheads) compared with wild-type littermates. A high power magnification of vertebral bodies is shown in the inset. (D) In situ hybridization analysis for the expression of Col2a1 and Col10a1 in the growth plates from wild-type and Sox8-deficient mice 2 d after birth showing normal chondrocyte differentiation in the absence of Sox8. (E) Analysis of chondrocyte proliferation by BrdU-incorporation assays at 1 wk old. No significant difference in the percentage of BrdU-positive cells was observed between the two groups. (F) Hematoxylin/eosin staining of tibial growth plates at 1 wk old. No difference in growth plate organization and thickness was observed between the groups. P, Proliferative zone, PH, prehypertrophic zone, H, hypertrophic zone. (G) Staining with alcian blue and alizarin red reveals a size reduction of Sox8-deficient clavicles at 6 wk old. (H) μCT imaging of the calvariae from 6-wk-old wild-type and Sox8-deficient mice showing hypomineralization in the absence of Sox8. The calvarial thickness is decreased in Sox8-deficient mice at 6 and 20 wk old. Values represent means ± SEM (n = 6). Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). **, P < 0.005.
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fig1: Analysis of endochondral and intramembranous ossification in Sox8-deficient mice. (A) Staining of wild-type (WT) and Sox8-deficient (−/−) skeletons with alcian blue and alizarin red at 17.5 dpc of embryonic development. No gross abnormalities were observed in the absence of Sox8. (B) Staining of undecalcified tibia sections with Toluidine blue and silver nitrate at 16.5 and 18.5 dpc, as well as in newborn wild-type and Sox8-deficient mice. No significant defects of endochondral ossification were observed in the absence of Sox8. (C) Radiographic analysis of skeletons from wild-type and Sox8-deficient mice at 6 wk old. The Sox8-deficient mice are smaller, show an increased radiolucency (arrows) and display hypoplastic clavicles (arrowheads) compared with wild-type littermates. A high power magnification of vertebral bodies is shown in the inset. (D) In situ hybridization analysis for the expression of Col2a1 and Col10a1 in the growth plates from wild-type and Sox8-deficient mice 2 d after birth showing normal chondrocyte differentiation in the absence of Sox8. (E) Analysis of chondrocyte proliferation by BrdU-incorporation assays at 1 wk old. No significant difference in the percentage of BrdU-positive cells was observed between the two groups. (F) Hematoxylin/eosin staining of tibial growth plates at 1 wk old. No difference in growth plate organization and thickness was observed between the groups. P, Proliferative zone, PH, prehypertrophic zone, H, hypertrophic zone. (G) Staining with alcian blue and alizarin red reveals a size reduction of Sox8-deficient clavicles at 6 wk old. (H) μCT imaging of the calvariae from 6-wk-old wild-type and Sox8-deficient mice showing hypomineralization in the absence of Sox8. The calvarial thickness is decreased in Sox8-deficient mice at 6 and 20 wk old. Values represent means ± SEM (n = 6). Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). **, P < 0.005.

Mentions: To determine whether Sox8 has a physiologic function in skeletal biology, we embarked on a full characterization of the skeletal phenotype of Sox8-deficient mice. We first studied their skeletal development and stained embryos with alcian blue and alizarin red without finding gross abnormalities compared with wild-type littermates (Fig. 1 A). To rule out subtle defects of endochondral ossification, we histologically analyzed the hindlimbs from wild-type and Sox8-deficient embryos at 16.5 and 18.5 dpc, as well as from newborn mice. Again, we did not observe significant differences between the two groups (Fig. 1 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)

Analysis of endochondral and intramembranous ossification in Sox8-deficient mice. (A) Staining of wild-type (WT) and Sox8-deficient (−/−) skeletons with alcian blue and alizarin red at 17.5 dpc of embryonic development. No gross abnormalities were observed in the absence of Sox8. (B) Staining of undecalcified tibia sections with Toluidine blue and silver nitrate at 16.5 and 18.5 dpc, as well as in newborn wild-type and Sox8-deficient mice. No significant defects of endochondral ossification were observed in the absence of Sox8. (C) Radiographic analysis of skeletons from wild-type and Sox8-deficient mice at 6 wk old. The Sox8-deficient mice are smaller, show an increased radiolucency (arrows) and display hypoplastic clavicles (arrowheads) compared with wild-type littermates. A high power magnification of vertebral bodies is shown in the inset. (D) In situ hybridization analysis for the expression of Col2a1 and Col10a1 in the growth plates from wild-type and Sox8-deficient mice 2 d after birth showing normal chondrocyte differentiation in the absence of Sox8. (E) Analysis of chondrocyte proliferation by BrdU-incorporation assays at 1 wk old. No significant difference in the percentage of BrdU-positive cells was observed between the two groups. (F) Hematoxylin/eosin staining of tibial growth plates at 1 wk old. No difference in growth plate organization and thickness was observed between the groups. P, Proliferative zone, PH, prehypertrophic zone, H, hypertrophic zone. (G) Staining with alcian blue and alizarin red reveals a size reduction of Sox8-deficient clavicles at 6 wk old. (H) μCT imaging of the calvariae from 6-wk-old wild-type and Sox8-deficient mice showing hypomineralization in the absence of Sox8. The calvarial thickness is decreased in Sox8-deficient mice at 6 and 20 wk old. Values represent means ± SEM (n = 6). Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). **, P < 0.005.
© Copyright Policy
Related In: Results  -  Collection

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fig1: Analysis of endochondral and intramembranous ossification in Sox8-deficient mice. (A) Staining of wild-type (WT) and Sox8-deficient (−/−) skeletons with alcian blue and alizarin red at 17.5 dpc of embryonic development. No gross abnormalities were observed in the absence of Sox8. (B) Staining of undecalcified tibia sections with Toluidine blue and silver nitrate at 16.5 and 18.5 dpc, as well as in newborn wild-type and Sox8-deficient mice. No significant defects of endochondral ossification were observed in the absence of Sox8. (C) Radiographic analysis of skeletons from wild-type and Sox8-deficient mice at 6 wk old. The Sox8-deficient mice are smaller, show an increased radiolucency (arrows) and display hypoplastic clavicles (arrowheads) compared with wild-type littermates. A high power magnification of vertebral bodies is shown in the inset. (D) In situ hybridization analysis for the expression of Col2a1 and Col10a1 in the growth plates from wild-type and Sox8-deficient mice 2 d after birth showing normal chondrocyte differentiation in the absence of Sox8. (E) Analysis of chondrocyte proliferation by BrdU-incorporation assays at 1 wk old. No significant difference in the percentage of BrdU-positive cells was observed between the two groups. (F) Hematoxylin/eosin staining of tibial growth plates at 1 wk old. No difference in growth plate organization and thickness was observed between the groups. P, Proliferative zone, PH, prehypertrophic zone, H, hypertrophic zone. (G) Staining with alcian blue and alizarin red reveals a size reduction of Sox8-deficient clavicles at 6 wk old. (H) μCT imaging of the calvariae from 6-wk-old wild-type and Sox8-deficient mice showing hypomineralization in the absence of Sox8. The calvarial thickness is decreased in Sox8-deficient mice at 6 and 20 wk old. Values represent means ± SEM (n = 6). Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). **, P < 0.005.
Mentions: To determine whether Sox8 has a physiologic function in skeletal biology, we embarked on a full characterization of the skeletal phenotype of Sox8-deficient mice. We first studied their skeletal development and stained embryos with alcian blue and alizarin red without finding gross abnormalities compared with wild-type littermates (Fig. 1 A). To rule out subtle defects of endochondral ossification, we histologically analyzed the hindlimbs from wild-type and Sox8-deficient embryos at 16.5 and 18.5 dpc, as well as from newborn mice. Again, we did not observe significant differences between the two groups (Fig. 1 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