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Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone.

Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DH, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T - PLoS ONE (2008)

Bottom Line: During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones.Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation.Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT
During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI) kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

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Pharmacologic TβRI inhibition increases BMD.DXA was used to measure BMD longitudinally for male (a, c, e, g) and female mice (b, d, f, h) treated with or without the TβRI inhibitor SD-208 at 20 mg/kg or 60 mg/kg. SD-208 treatment at the 60 mg/kg dose caused an increase in total body (a, b) tibia (c, d), femur (e, f), and lumbar spine (g, h) BMD. SD-208 at the 20 mg/kg dose increased femoral BMD in female mice (f). Data represent mean±SEM (p<0.05, as determined by two-way analysis of variance (ANOVA).
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pone-0005275-g002: Pharmacologic TβRI inhibition increases BMD.DXA was used to measure BMD longitudinally for male (a, c, e, g) and female mice (b, d, f, h) treated with or without the TβRI inhibitor SD-208 at 20 mg/kg or 60 mg/kg. SD-208 treatment at the 60 mg/kg dose caused an increase in total body (a, b) tibia (c, d), femur (e, f), and lumbar spine (g, h) BMD. SD-208 at the 20 mg/kg dose increased femoral BMD in female mice (f). Data represent mean±SEM (p<0.05, as determined by two-way analysis of variance (ANOVA).

Mentions: Longitudinal examination of the bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) showed the normal increase in BMD between 1 and 2.5 months of age. Accordingly, vehicle-treated male and female mice showed an increase of 21.8% and 29.6%, respectively, in whole body BMD after 6 weeks (Fig. 2a, 2b). Although low dose SD-208 did not affect whole body BMD, both male and female mice treated with high dose SD-208, showed significantly greater bone accrual over the same time period, with an additional 4.12% increase in male (p<0.001) and 5.2% increase in female (p<0.001) whole body BMD. The SD-208-induced increase in whole body BMD was comparable to that observed following an 8-week treatment with bisphosphonates, which can increase whole body BMD by 5% [31].


Pharmacologic inhibition of the TGF-beta type I receptor kinase has anabolic and anti-catabolic effects on bone.

Mohammad KS, Chen CG, Balooch G, Stebbins E, McKenna CR, Davis H, Niewolna M, Peng XH, Nguyen DH, Ionova-Martin SS, Bracey JW, Hogue WR, Wong DH, Ritchie RO, Suva LJ, Derynck R, Guise TA, Alliston T - PLoS ONE (2008)

Pharmacologic TβRI inhibition increases BMD.DXA was used to measure BMD longitudinally for male (a, c, e, g) and female mice (b, d, f, h) treated with or without the TβRI inhibitor SD-208 at 20 mg/kg or 60 mg/kg. SD-208 treatment at the 60 mg/kg dose caused an increase in total body (a, b) tibia (c, d), femur (e, f), and lumbar spine (g, h) BMD. SD-208 at the 20 mg/kg dose increased femoral BMD in female mice (f). Data represent mean±SEM (p<0.05, as determined by two-way analysis of variance (ANOVA).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2666804&req=5

pone-0005275-g002: Pharmacologic TβRI inhibition increases BMD.DXA was used to measure BMD longitudinally for male (a, c, e, g) and female mice (b, d, f, h) treated with or without the TβRI inhibitor SD-208 at 20 mg/kg or 60 mg/kg. SD-208 treatment at the 60 mg/kg dose caused an increase in total body (a, b) tibia (c, d), femur (e, f), and lumbar spine (g, h) BMD. SD-208 at the 20 mg/kg dose increased femoral BMD in female mice (f). Data represent mean±SEM (p<0.05, as determined by two-way analysis of variance (ANOVA).
Mentions: Longitudinal examination of the bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) showed the normal increase in BMD between 1 and 2.5 months of age. Accordingly, vehicle-treated male and female mice showed an increase of 21.8% and 29.6%, respectively, in whole body BMD after 6 weeks (Fig. 2a, 2b). Although low dose SD-208 did not affect whole body BMD, both male and female mice treated with high dose SD-208, showed significantly greater bone accrual over the same time period, with an additional 4.12% increase in male (p<0.001) and 5.2% increase in female (p<0.001) whole body BMD. The SD-208-induced increase in whole body BMD was comparable to that observed following an 8-week treatment with bisphosphonates, which can increase whole body BMD by 5% [31].

Bottom Line: During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones.Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation.Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT
During development, growth factors and hormones cooperate to establish the unique sizes, shapes and material properties of individual bones. Among these, TGF-beta has been shown to developmentally regulate bone mass and bone matrix properties. However, the mechanisms that control postnatal skeletal integrity in a dynamic biological and mechanical environment are distinct from those that regulate bone development. In addition, despite advances in understanding the roles of TGF-beta signaling in osteoblasts and osteoclasts, the net effects of altered postnatal TGF-beta signaling on bone remain unclear. To examine the role of TGF-beta in the maintenance of the postnatal skeleton, we evaluated the effects of pharmacological inhibition of the TGF-beta type I receptor (TbetaRI) kinase on bone mass, architecture and material properties. Inhibition of TbetaRI function increased bone mass and multiple aspects of bone quality, including trabecular bone architecture and macro-mechanical behavior of vertebral bone. TbetaRI inhibitors achieved these effects by increasing osteoblast differentiation and bone formation, while reducing osteoclast differentiation and bone resorption. Furthermore, they induced the expression of Runx2 and EphB4, which promote osteoblast differentiation, and ephrinB2, which antagonizes osteoclast differentiation. Through these anabolic and anti-catabolic effects, TbetaRI inhibitors coordinate changes in multiple bone parameters, including bone mass, architecture, matrix mineral concentration and material properties, that collectively increase bone fracture resistance. Therefore, TbetaRI inhibitors may be effective in treating conditions of skeletal fragility.

Show MeSH
Related in: MedlinePlus