title: 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)(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.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Idelevich
authors.forename: Michael
authors.initials: M
authors.lastname: Kerschnitzki
authors.forename: Ron
authors.initials: R
authors.lastname: Shahar
authors.forename: Efrat
authors.initials: E
authors.lastname: Monsonego-Ornan
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects / Q000473:pathology; D006132:Growth Plate / Q000187:drug effects / Q000254:growth & development*; D006984:Hypertrophy; D007668:Kidney / Q000187:drug effects* / Q000502:physiology*; D007677:Kidney Function Tests; D008297:Male; D010012:Osteogenesis / Q000187:drug effects; D016062:Porosity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000033:anatomy & histology* / Q000187:drug effects
chemical_list: D015415:Biomarkers; D002117:Calcitriol