Limits...
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.

Show MeSH

Related in: MedlinePlus

Increased cortical porosity in Col1a1-Sox8 transgenic mice. (A) Von Kossa staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old shows that transgenic mice display extensive cortical porosity. Toluidine blue staining reveals a severely impaired bone formation in Col1a1-Sox8 transgenic mice. Note that the typical morphology of osteoblasts (located above the dotted red line) and osteocytes (arrowheads) is not observed in transgenic mice. Quantification of osteoblast number was not possible in transgenic mice, because they did not contain the characteristic cuboidal osteoblasts, in contrast to wild-type littermates. (B) Von Kossa and Toluidine blue staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 10 wk old reveals a partial recovery from the severe phenotype, although the number of osteoblasts is still significantly reduced in the transgenic mice. (C) Immunohistochemistry using an antibody against type I collagen shows that the amount of this protein is largely reduced in cortical bone of transgenic mice at 2 wk old. (D) Northern blot expression analysis using RNA from calvariae of wild-type and Col1a1-Sox8 transgenic mice at different ages reveals that the expression of the transgene (arrowhead) is strongly down-regulated over time compared with the endogenous Sox8 expression (arrow). (E) Cross-sectional μCT scans from femora of wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice confirming the increased cortical porosity in transgenic mice at 2 wk old. Force to failure as determined by three-point bending assays is significantly reduced in transgenic femora indicating decreased biomechanical stability. (F) A spontaneous fracture of the humerus (white arrow) was observed by contact radiography in a Col1a1-Sox8 transgenic founder (left). Mallory staining of an undecalcified section (right) shows that callus formation occurred at the fracture site (black arrow). Values represent means ± SEM. Asterisks indicate a statistically significant difference between the two groups (n = 5). *, P < 0.05; **, P < 0.005.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2171778&req=5

fig7: Increased cortical porosity in Col1a1-Sox8 transgenic mice. (A) Von Kossa staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old shows that transgenic mice display extensive cortical porosity. Toluidine blue staining reveals a severely impaired bone formation in Col1a1-Sox8 transgenic mice. Note that the typical morphology of osteoblasts (located above the dotted red line) and osteocytes (arrowheads) is not observed in transgenic mice. Quantification of osteoblast number was not possible in transgenic mice, because they did not contain the characteristic cuboidal osteoblasts, in contrast to wild-type littermates. (B) Von Kossa and Toluidine blue staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 10 wk old reveals a partial recovery from the severe phenotype, although the number of osteoblasts is still significantly reduced in the transgenic mice. (C) Immunohistochemistry using an antibody against type I collagen shows that the amount of this protein is largely reduced in cortical bone of transgenic mice at 2 wk old. (D) Northern blot expression analysis using RNA from calvariae of wild-type and Col1a1-Sox8 transgenic mice at different ages reveals that the expression of the transgene (arrowhead) is strongly down-regulated over time compared with the endogenous Sox8 expression (arrow). (E) Cross-sectional μCT scans from femora of wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice confirming the increased cortical porosity in transgenic mice at 2 wk old. Force to failure as determined by three-point bending assays is significantly reduced in transgenic femora indicating decreased biomechanical stability. (F) A spontaneous fracture of the humerus (white arrow) was observed by contact radiography in a Col1a1-Sox8 transgenic founder (left). Mallory staining of an undecalcified section (right) shows that callus formation occurred at the fracture site (black arrow). Values represent means ± SEM. Asterisks indicate a statistically significant difference between the two groups (n = 5). *, P < 0.05; **, P < 0.005.

Mentions: The phenotype of the Col1a1-Sox8 transgenic mice was especially pronounced in cortical bone. In fact, Von Kossa staining of undecalcified tibia sections revealed an incomplete cortical bone formation in Col1a1-Sox8 transgenic mice at 2 wk old (Fig. 7 A). Toluidine blue staining showed that in wild-type mice cortical bone was correctly organized with several osteocytes of flattened appearance and large teams of osteoblasts forming new bone. In contrast, the cortical bone matrix of transgenic mice was disorganized, and osteoblast differentiation was obviously impaired. Therefore, histomorphometric quantification of osteoblast indices was not possible in Col1a1-Sox8 transgenic mice at that age, because bone-forming cells with the characteristic cuboidal appearance were not detectable (Fig. 7 A). At 10 wk old this phenotype was still present, albeit less severe. Osteoblasts were now quantifiable, but their number was significantly reduced by 45% (Fig. 7 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)

Increased cortical porosity in Col1a1-Sox8 transgenic mice. (A) Von Kossa staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old shows that transgenic mice display extensive cortical porosity. Toluidine blue staining reveals a severely impaired bone formation in Col1a1-Sox8 transgenic mice. Note that the typical morphology of osteoblasts (located above the dotted red line) and osteocytes (arrowheads) is not observed in transgenic mice. Quantification of osteoblast number was not possible in transgenic mice, because they did not contain the characteristic cuboidal osteoblasts, in contrast to wild-type littermates. (B) Von Kossa and Toluidine blue staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 10 wk old reveals a partial recovery from the severe phenotype, although the number of osteoblasts is still significantly reduced in the transgenic mice. (C) Immunohistochemistry using an antibody against type I collagen shows that the amount of this protein is largely reduced in cortical bone of transgenic mice at 2 wk old. (D) Northern blot expression analysis using RNA from calvariae of wild-type and Col1a1-Sox8 transgenic mice at different ages reveals that the expression of the transgene (arrowhead) is strongly down-regulated over time compared with the endogenous Sox8 expression (arrow). (E) Cross-sectional μCT scans from femora of wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice confirming the increased cortical porosity in transgenic mice at 2 wk old. Force to failure as determined by three-point bending assays is significantly reduced in transgenic femora indicating decreased biomechanical stability. (F) A spontaneous fracture of the humerus (white arrow) was observed by contact radiography in a Col1a1-Sox8 transgenic founder (left). Mallory staining of an undecalcified section (right) shows that callus formation occurred at the fracture site (black arrow). Values represent means ± SEM. Asterisks indicate a statistically significant difference between the two groups (n = 5). *, P < 0.05; **, P < 0.005.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171778&req=5

fig7: Increased cortical porosity in Col1a1-Sox8 transgenic mice. (A) Von Kossa staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 2 wk old shows that transgenic mice display extensive cortical porosity. Toluidine blue staining reveals a severely impaired bone formation in Col1a1-Sox8 transgenic mice. Note that the typical morphology of osteoblasts (located above the dotted red line) and osteocytes (arrowheads) is not observed in transgenic mice. Quantification of osteoblast number was not possible in transgenic mice, because they did not contain the characteristic cuboidal osteoblasts, in contrast to wild-type littermates. (B) Von Kossa and Toluidine blue staining of undecalcified tibia sections from wild-type and Col1a1-Sox8 transgenic mice at 10 wk old reveals a partial recovery from the severe phenotype, although the number of osteoblasts is still significantly reduced in the transgenic mice. (C) Immunohistochemistry using an antibody against type I collagen shows that the amount of this protein is largely reduced in cortical bone of transgenic mice at 2 wk old. (D) Northern blot expression analysis using RNA from calvariae of wild-type and Col1a1-Sox8 transgenic mice at different ages reveals that the expression of the transgene (arrowhead) is strongly down-regulated over time compared with the endogenous Sox8 expression (arrow). (E) Cross-sectional μCT scans from femora of wild-type (WT) and Col1a1-Sox8 transgenic (TG) mice confirming the increased cortical porosity in transgenic mice at 2 wk old. Force to failure as determined by three-point bending assays is significantly reduced in transgenic femora indicating decreased biomechanical stability. (F) A spontaneous fracture of the humerus (white arrow) was observed by contact radiography in a Col1a1-Sox8 transgenic founder (left). Mallory staining of an undecalcified section (right) shows that callus formation occurred at the fracture site (black arrow). Values represent means ± SEM. Asterisks indicate a statistically significant difference between the two groups (n = 5). *, P < 0.05; **, P < 0.005.
Mentions: The phenotype of the Col1a1-Sox8 transgenic mice was especially pronounced in cortical bone. In fact, Von Kossa staining of undecalcified tibia sections revealed an incomplete cortical bone formation in Col1a1-Sox8 transgenic mice at 2 wk old (Fig. 7 A). Toluidine blue staining showed that in wild-type mice cortical bone was correctly organized with several osteocytes of flattened appearance and large teams of osteoblasts forming new bone. In contrast, the cortical bone matrix of transgenic mice was disorganized, and osteoblast differentiation was obviously impaired. Therefore, histomorphometric quantification of osteoblast indices was not possible in Col1a1-Sox8 transgenic mice at that age, because bone-forming cells with the characteristic cuboidal appearance were not detectable (Fig. 7 A). At 10 wk old this phenotype was still present, albeit less severe. Osteoblasts were now quantifiable, but their number was significantly reduced by 45% (Fig. 7 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