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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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Osteopenia in Sox8-deficient mice. (A) Von Kossa staining of undecalcified vertebral sections and quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume) reveals an osteopenic phenotype in Sox8-deficient mice at 6 wk old. (B) The same was observed in sections from vertebral bodies and tibiae at 20 wk old. (C) Histomorphometric quantification shows that trabecular number (Tb.N) and trabecular thickness (Tb.Th) are significantly decreased in Sox8-deficient mice (gray bars) compared with wild-type littermates (white bars) at both ages. (D) Histomorphometric quantification of trabecular bone formation parameters. The number of cuboidal osteoblasts (Ob.N/BPm, osteoblast number per bone perimeter) is strongly decreased in Sox8-deficient mice compared with wild-type littermates. This results in a significant reduction of the bone formation rate as determined by dynamic histomorphometry after dual calcein injection. (E) Quantification of bone resorption parameters. Although the numbers of osteoclasts (N.Oc/BPm, osteoclast number per bone perimeter) are decreased in Sox8-deficient mice at 20 wk old, there is no significant change in bone resorption as determined by measuring the urinary deoxypyridinoline (Dpd) cross-links. Values represent means ± SEM. Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). *, P < 0.05; **, P < 0.005.
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fig2: Osteopenia in Sox8-deficient mice. (A) Von Kossa staining of undecalcified vertebral sections and quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume) reveals an osteopenic phenotype in Sox8-deficient mice at 6 wk old. (B) The same was observed in sections from vertebral bodies and tibiae at 20 wk old. (C) Histomorphometric quantification shows that trabecular number (Tb.N) and trabecular thickness (Tb.Th) are significantly decreased in Sox8-deficient mice (gray bars) compared with wild-type littermates (white bars) at both ages. (D) Histomorphometric quantification of trabecular bone formation parameters. The number of cuboidal osteoblasts (Ob.N/BPm, osteoblast number per bone perimeter) is strongly decreased in Sox8-deficient mice compared with wild-type littermates. This results in a significant reduction of the bone formation rate as determined by dynamic histomorphometry after dual calcein injection. (E) Quantification of bone resorption parameters. Although the numbers of osteoclasts (N.Oc/BPm, osteoclast number per bone perimeter) are decreased in Sox8-deficient mice at 20 wk old, there is no significant change in bone resorption as determined by measuring the urinary deoxypyridinoline (Dpd) cross-links. Values represent means ± SEM. Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). *, P < 0.05; **, P < 0.005.

Mentions: We next performed a complete histomorphometric analysis of bone remodeling parameters in Sox8-deficient mice and wild-type littermates at 6 and 20 wk old. Von Kossa staining of undecalcified sections confirmed the osteopenia in Sox8-deficient mice at both ages (Fig. 2, A and B). The histomorphometric analysis revealed that the trabecular bone volume in vertebral bodies and tibiae of Sox8-deficient mice was decreased by >30% compared with wild-type littermates. Further analysis demonstrated that trabecular number and trabecular thickness were significantly decreased in Sox8-deficient mice at both ages (Fig. 2 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)

Osteopenia in Sox8-deficient mice. (A) Von Kossa staining of undecalcified vertebral sections and quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume) reveals an osteopenic phenotype in Sox8-deficient mice at 6 wk old. (B) The same was observed in sections from vertebral bodies and tibiae at 20 wk old. (C) Histomorphometric quantification shows that trabecular number (Tb.N) and trabecular thickness (Tb.Th) are significantly decreased in Sox8-deficient mice (gray bars) compared with wild-type littermates (white bars) at both ages. (D) Histomorphometric quantification of trabecular bone formation parameters. The number of cuboidal osteoblasts (Ob.N/BPm, osteoblast number per bone perimeter) is strongly decreased in Sox8-deficient mice compared with wild-type littermates. This results in a significant reduction of the bone formation rate as determined by dynamic histomorphometry after dual calcein injection. (E) Quantification of bone resorption parameters. Although the numbers of osteoclasts (N.Oc/BPm, osteoclast number per bone perimeter) are decreased in Sox8-deficient mice at 20 wk old, there is no significant change in bone resorption as determined by measuring the urinary deoxypyridinoline (Dpd) cross-links. Values represent means ± SEM. Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). *, P < 0.05; **, P < 0.005.
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fig2: Osteopenia in Sox8-deficient mice. (A) Von Kossa staining of undecalcified vertebral sections and quantification of the trabecular bone volume (BV/TV, bone volume per tissue volume) reveals an osteopenic phenotype in Sox8-deficient mice at 6 wk old. (B) The same was observed in sections from vertebral bodies and tibiae at 20 wk old. (C) Histomorphometric quantification shows that trabecular number (Tb.N) and trabecular thickness (Tb.Th) are significantly decreased in Sox8-deficient mice (gray bars) compared with wild-type littermates (white bars) at both ages. (D) Histomorphometric quantification of trabecular bone formation parameters. The number of cuboidal osteoblasts (Ob.N/BPm, osteoblast number per bone perimeter) is strongly decreased in Sox8-deficient mice compared with wild-type littermates. This results in a significant reduction of the bone formation rate as determined by dynamic histomorphometry after dual calcein injection. (E) Quantification of bone resorption parameters. Although the numbers of osteoclasts (N.Oc/BPm, osteoclast number per bone perimeter) are decreased in Sox8-deficient mice at 20 wk old, there is no significant change in bone resorption as determined by measuring the urinary deoxypyridinoline (Dpd) cross-links. Values represent means ± SEM. Asterisks indicate statistically significant differences as determined by t test between the two groups (n = 6). *, P < 0.05; **, P < 0.005.
Mentions: We next performed a complete histomorphometric analysis of bone remodeling parameters in Sox8-deficient mice and wild-type littermates at 6 and 20 wk old. Von Kossa staining of undecalcified sections confirmed the osteopenia in Sox8-deficient mice at both ages (Fig. 2, A and B). The histomorphometric analysis revealed that the trabecular bone volume in vertebral bodies and tibiae of Sox8-deficient mice was decreased by >30% compared with wild-type littermates. Further analysis demonstrated that trabecular number and trabecular thickness were significantly decreased in Sox8-deficient mice at both ages (Fig. 2 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