1,25(OH)2D3 Alters Growth Plate Maturation and Bone Architecture in Young Rats with Normal Renal Function

Abstract

Whereas detrimental effects of vitamin D deficiency are known over century, the effects of vitamin D receptor activation by 1,25(OH)2D3, the principal hormonal form of vitamin D, on the growing bone and its growth plate are less clear. Currently, 1,25(OH)2D3 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)2D3 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)2D3 for one week, or intermittent 3 µg/kg 1,25(OH)2D3 for one month. Histological analysis revealed narrower tibial growth plates, predominantly in the hypertrophic zone of 1,25(OH)2D3-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)2D3 increased chondrocyte proliferation and apoptosis in terminal hypertrophic cells. In vitro treatment of the chondrocytic cell line ATDC5 with 1,25(OH)2D3 lowered differentiation and increased proliferation dose and time-dependently. Micro-CT analysis of femurs from 1-week 1,25(OH)2D3-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)2D3 on intracortical bone formation. This study shows negative effects of 1,25(OH)2D3 on growth plate and bone which may contribute to the exacerbation of MBD in the CKD pediatric patients.

Roux-en-Y gastric bypass surgery reduces bone mineral density and induces metabolic acidosis in rats

“…Vitamin D deficiency or lack of the VDR lead to characteristic changes in the epiphyseal growth plates, i.e., growth plate widening with disorganized structure and accumulation of immature, unmineralized bone mass (8). 1,25(OH) 2 D on the other hand reduces growth plate width in young rats (23). In our study, the histological evaluation of the epiphyseal growth plate in the proximal tibia revealed a trend toward narrowing of the growth plates in adult RYGB rats (P Ͻ 0.1; Fig.…”

“…For the measurement of growth plate width, images of the total growth plate were obtained at a magnification of 10 ϫ 10. Seven vertical (perpendicular to chondro-osseous junction) lines were drawn throughout the growth plate and measured; growth plate width was calculated as an average of these seven measurements (23).…”

Histochemical examination of the effects of high-dose 1,25(OH)2D3 on bone remodeling in young growing rats

“…Calcitriol, the activated form of vitamin D3, has opposing effects on osteoblast differentiation (Hicok et al 1998;Lohmann et al 2000;Li et al 2008). Furthermore, supraphysiological doses of 1,25(OH) 2 D 3 inhibit cancellous bone formation, exerting a negative influence on bone quality, beginning from 1-week post-administration and intensifying after 1 month of exposure (Idelevich et al 2011). In the present study, we noticed that even at a physiologically-high dose, 1,25(OH) 2 D 3 inhibited osteogenesis, inhibited the activity of osteoblasts and reduced bone formation in vivo.…”

The Paracrine Feedback Loop Between Vitamin D3 (1,25(OH)2D3) and PTHrP in Prehypertrophic Chondrocytes

“…5 and 7C,D). This is by no means a new finding, since 1,25(OH) 2 D 3 has been shown to inhibit terminal chondrocyte differentiation both in vitro and in vivo (Kato et al, 1990;Drissi et al, 2002;Idelevich et al, 2011;Castillo et al, 2012). In addition, VDR silencing in 1,25(OH) 2 D 3 -treated ATDC5 cells only partially reversed the anti-hypertrophic effects of 1,25(OH) 2 D 3 : it prevented the inhibitory effect of 1,25(OH) 2 D 3 on Pthr1 gene expression, but it did not affect collagen type X expression ( Fig.…”