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1,25(OH)2D3 alters growth plate maturation and bone architecture in young rats with normal renal function.

Idelevich A, Kerschnitzki M, Shahar R, Monsonego-Ornan E - PLoS ONE (2011)

Bottom Line: Concomitant with altered chondrocyte maturation, 1,25(OH)(2)D(3) increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells.In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)(2)D(3) lowered differentiation and increased proliferation dose and time-dependently.Micro-CT analysis of femurs from 1-week 1,25(OH)(2)D(3)-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot, Israel.

ABSTRACT
Whereas detrimental effects of vitamin D deficiency are known over century, the effects of vitamin D receptor activation by 1,25(OH)(2)D(3), the principal hormonal form of vitamin D, on the growing bone and its growth plate are less clear. Currently, 1,25(OH)(2)D(3) is used in pediatric patients with chronic kidney disease and mineral and bone disorder (CKD-MBD) and is strongly associated with growth retardation. Here, we investigate the effect of 1,25(OH)(2)D(3) treatment on bone development in normal young rats, unrelated to renal insufficiency. Young rats received daily i.p. injections of 1 µg/kg 1,25(OH)(2)D(3) for one week, or intermittent 3 µg/kg 1,25(OH)(2)D(3) for one month. Histological analysis revealed narrower tibial growth plates, predominantly in the hypertrophic zone of 1,25(OH)(2)D(3)-treated animals in both experimental protocols. This phenotype was supported by narrower distribution of aggrecan, collagens II and X mRNA, shown by in situ hybridization. Concomitant with altered chondrocyte maturation, 1,25(OH)(2)D(3) increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells. In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)(2)D(3) lowered differentiation and increased proliferation dose and time-dependently. Micro-CT analysis of femurs from 1-week 1,25(OH)(2)D(3)-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone. Evaluation of fluorochrome binding with confocal microscopy revealed inhibiting effects of 1,25(OH)(2)D(3) on intracortical bone formation. This study shows negative effects of 1,25(OH)(2)D(3) on growth plate and bone which may contribute to the exacerbation of MBD in the CKD pediatric patients.

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1-month administration of 1,25(OH)2D3 alters cortical bone, but not trabecular bone, architecture by reducing thickness and elevating porosity in young rats.4 weeks old male Spague Dawley rats received i.p. injections of 3 µg/kg 1,25(OH)2D3 (n = 6, VD) or vehicle (n = 6, Ctr) on alternating days, three times a week for a period of 30 days. Femurs were removed and subjected to μ-CT scan from proximal femoral metaphysis to the mid-point of diaphysis, using 13.4 µm voxel size resolution and 4000 ms laser exposure. (A) 3D images of cortical bones. Note the reduced cortical thickness and elevated porosity in the 1,25(OH)2D3-treated group compared to control, as indicated by green arrows. (B) 3D images of trabecular bones. (C) Cortical morphological parameters. (D) Trabecular bone morphological parameters. For abbreviations see figure 4. Results are shown as means (n = 6) ± SE. * denotes p<0.05 comparing 1,25(OH)2D3-treated to control group. (E) 3D images of total scan cut by coronal plane (marked red). Note the reduced thickness and higher presence of pores in the cortical bone of 1,25(OH)2D3-treated group compared to control group, as indicated by green arrows.
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pone-0020772-g005: 1-month administration of 1,25(OH)2D3 alters cortical bone, but not trabecular bone, architecture by reducing thickness and elevating porosity in young rats.4 weeks old male Spague Dawley rats received i.p. injections of 3 µg/kg 1,25(OH)2D3 (n = 6, VD) or vehicle (n = 6, Ctr) on alternating days, three times a week for a period of 30 days. Femurs were removed and subjected to μ-CT scan from proximal femoral metaphysis to the mid-point of diaphysis, using 13.4 µm voxel size resolution and 4000 ms laser exposure. (A) 3D images of cortical bones. Note the reduced cortical thickness and elevated porosity in the 1,25(OH)2D3-treated group compared to control, as indicated by green arrows. (B) 3D images of trabecular bones. (C) Cortical morphological parameters. (D) Trabecular bone morphological parameters. For abbreviations see figure 4. Results are shown as means (n = 6) ± SE. * denotes p<0.05 comparing 1,25(OH)2D3-treated to control group. (E) 3D images of total scan cut by coronal plane (marked red). Note the reduced thickness and higher presence of pores in the cortical bone of 1,25(OH)2D3-treated group compared to control group, as indicated by green arrows.

Mentions: To our knowledge the effects of 1,25(OH)2D3 on young bone during rapid growth under normal physiological conditions were not previously examined using high-resolution imaging technologies. In this study we used microcomputed tomography (micro-CT) technique to evaluate whether alterations in the growth plate coincided with alterations in three-dimentional bone structure. 1-week administration of 1,25(OH)2D3 resulted in 14% lower cortical bone thickness (Co.Th.) compared to control, and the effect exacerbated to 45% reduction after 1-month 1,25(OH)2D3 treatment (Fig. 4A,C, 5A,C). No significant changes in the total cross-sectional area (T.Ar.), cortical bone area (Ct.Ar.) and medullary area (M.Ar.) were observed after 1-week administration, whereas 1-month 1,25(OH)2D3 group showed 28% reduction in Ct.Ar and 22% increase in the M.Ar, indicating thinner cortical femurs. Notably, 1,25(OH)2D3 triggered a significant reduction in bone volume over total volume (BV/TV) which fell to 7% lower than control during 1-month regimen. As BV/TV represents the relative ratio between bone and open space, the reduction BV/TV resulted in reciprocal 138% elevation in the percent cortical porosity (Ct.Po.) after 1-week (BV/TV of VD 96.9% compared to Ctr 98.6%) and 416% elevation after 1-month (BV/TV of VD 91.5% compared to Ctr 98.3%) 1,25(OH)2D3 treatment (Fig. 4C, 5C). Comparison of Ct.Po. between the bones of the control groups showed no significant differences, indicating unchanged bone volume and pore volume fractions over three week growth time. The total volume of pores increased by 117% after 1-week 1,25(OH)2D3 and by 295% after 1-month 1,25(OH)2D3, whereas the number of closed pores ((Po.N.(cl)), which accounts for small fraction of total pores, escalated from 258% to 400% higher than the respective control groups (Fig. 4C, 5C). The presence of 1,25(OH)2D3-elevated cortical pores is evident in the 3D model representations, indicated by arrows (Fig. 4A,E, 5A,E). These observations point toward a negative influence of 1,25(OH)2D3 on bone quality, starting from 1-week administration and intensifying by 1-month exposure.


1,25(OH)2D3 alters growth plate maturation and bone architecture in young rats with normal renal function.

Idelevich A, Kerschnitzki M, Shahar R, Monsonego-Ornan E - PLoS ONE (2011)

1-month administration of 1,25(OH)2D3 alters cortical bone, but not trabecular bone, architecture by reducing thickness and elevating porosity in young rats.4 weeks old male Spague Dawley rats received i.p. injections of 3 µg/kg 1,25(OH)2D3 (n = 6, VD) or vehicle (n = 6, Ctr) on alternating days, three times a week for a period of 30 days. Femurs were removed and subjected to μ-CT scan from proximal femoral metaphysis to the mid-point of diaphysis, using 13.4 µm voxel size resolution and 4000 ms laser exposure. (A) 3D images of cortical bones. Note the reduced cortical thickness and elevated porosity in the 1,25(OH)2D3-treated group compared to control, as indicated by green arrows. (B) 3D images of trabecular bones. (C) Cortical morphological parameters. (D) Trabecular bone morphological parameters. For abbreviations see figure 4. Results are shown as means (n = 6) ± SE. * denotes p<0.05 comparing 1,25(OH)2D3-treated to control group. (E) 3D images of total scan cut by coronal plane (marked red). Note the reduced thickness and higher presence of pores in the cortical bone of 1,25(OH)2D3-treated group compared to control group, as indicated by green arrows.
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Related In: Results  -  Collection

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pone-0020772-g005: 1-month administration of 1,25(OH)2D3 alters cortical bone, but not trabecular bone, architecture by reducing thickness and elevating porosity in young rats.4 weeks old male Spague Dawley rats received i.p. injections of 3 µg/kg 1,25(OH)2D3 (n = 6, VD) or vehicle (n = 6, Ctr) on alternating days, three times a week for a period of 30 days. Femurs were removed and subjected to μ-CT scan from proximal femoral metaphysis to the mid-point of diaphysis, using 13.4 µm voxel size resolution and 4000 ms laser exposure. (A) 3D images of cortical bones. Note the reduced cortical thickness and elevated porosity in the 1,25(OH)2D3-treated group compared to control, as indicated by green arrows. (B) 3D images of trabecular bones. (C) Cortical morphological parameters. (D) Trabecular bone morphological parameters. For abbreviations see figure 4. Results are shown as means (n = 6) ± SE. * denotes p<0.05 comparing 1,25(OH)2D3-treated to control group. (E) 3D images of total scan cut by coronal plane (marked red). Note the reduced thickness and higher presence of pores in the cortical bone of 1,25(OH)2D3-treated group compared to control group, as indicated by green arrows.
Mentions: To our knowledge the effects of 1,25(OH)2D3 on young bone during rapid growth under normal physiological conditions were not previously examined using high-resolution imaging technologies. In this study we used microcomputed tomography (micro-CT) technique to evaluate whether alterations in the growth plate coincided with alterations in three-dimentional bone structure. 1-week administration of 1,25(OH)2D3 resulted in 14% lower cortical bone thickness (Co.Th.) compared to control, and the effect exacerbated to 45% reduction after 1-month 1,25(OH)2D3 treatment (Fig. 4A,C, 5A,C). No significant changes in the total cross-sectional area (T.Ar.), cortical bone area (Ct.Ar.) and medullary area (M.Ar.) were observed after 1-week administration, whereas 1-month 1,25(OH)2D3 group showed 28% reduction in Ct.Ar and 22% increase in the M.Ar, indicating thinner cortical femurs. Notably, 1,25(OH)2D3 triggered a significant reduction in bone volume over total volume (BV/TV) which fell to 7% lower than control during 1-month regimen. As BV/TV represents the relative ratio between bone and open space, the reduction BV/TV resulted in reciprocal 138% elevation in the percent cortical porosity (Ct.Po.) after 1-week (BV/TV of VD 96.9% compared to Ctr 98.6%) and 416% elevation after 1-month (BV/TV of VD 91.5% compared to Ctr 98.3%) 1,25(OH)2D3 treatment (Fig. 4C, 5C). Comparison of Ct.Po. between the bones of the control groups showed no significant differences, indicating unchanged bone volume and pore volume fractions over three week growth time. The total volume of pores increased by 117% after 1-week 1,25(OH)2D3 and by 295% after 1-month 1,25(OH)2D3, whereas the number of closed pores ((Po.N.(cl)), which accounts for small fraction of total pores, escalated from 258% to 400% higher than the respective control groups (Fig. 4C, 5C). The presence of 1,25(OH)2D3-elevated cortical pores is evident in the 3D model representations, indicated by arrows (Fig. 4A,E, 5A,E). These observations point toward a negative influence of 1,25(OH)2D3 on bone quality, starting from 1-week administration and intensifying by 1-month exposure.

Bottom Line: Concomitant with altered chondrocyte maturation, 1,25(OH)(2)D(3) increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells.In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)(2)D(3) lowered differentiation and increased proliferation dose and time-dependently.Micro-CT analysis of femurs from 1-week 1,25(OH)(2)D(3)-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot, Israel.

ABSTRACT
Whereas detrimental effects of vitamin D deficiency are known over century, the effects of vitamin D receptor activation by 1,25(OH)(2)D(3), the principal hormonal form of vitamin D, on the growing bone and its growth plate are less clear. Currently, 1,25(OH)(2)D(3) is used in pediatric patients with chronic kidney disease and mineral and bone disorder (CKD-MBD) and is strongly associated with growth retardation. Here, we investigate the effect of 1,25(OH)(2)D(3) treatment on bone development in normal young rats, unrelated to renal insufficiency. Young rats received daily i.p. injections of 1 µg/kg 1,25(OH)(2)D(3) for one week, or intermittent 3 µg/kg 1,25(OH)(2)D(3) for one month. Histological analysis revealed narrower tibial growth plates, predominantly in the hypertrophic zone of 1,25(OH)(2)D(3)-treated animals in both experimental protocols. This phenotype was supported by narrower distribution of aggrecan, collagens II and X mRNA, shown by in situ hybridization. Concomitant with altered chondrocyte maturation, 1,25(OH)(2)D(3) increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells. In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)(2)D(3) lowered differentiation and increased proliferation dose and time-dependently. Micro-CT analysis of femurs from 1-week 1,25(OH)(2)D(3)-treated group revealed reduced cortical thickness, elevated cortical porosity, and higher trabecular number and thickness. 1-month administration resulted in a similar cortical phenotype but without effect on trabecular bone. Evaluation of fluorochrome binding with confocal microscopy revealed inhibiting effects of 1,25(OH)(2)D(3) on intracortical bone formation. This study shows negative effects of 1,25(OH)(2)D(3) on growth plate and bone which may contribute to the exacerbation of MBD in the CKD pediatric patients.

Show MeSH
Related in: MedlinePlus