title: Histochemical examination of the effects of high-dose 1,25(OH)2D3 on bone remodeling in young growing rats.
abstract: Vitamin D has an anabolic effect on bone developmental processes and is involved in maintaining skeletal integrity. In recent years, pediatric cases of vitamin D intoxication have attracted attention. Therefore, the aim of this study was to investigate the influence of long-term administration of physiologically-high-dose calcitriol (1,25(OH)2D3) on bone remodeling in young developing rats. Neonatal rats received once-daily subcutaneous injection of calcitriol (250 ng/kg body weight), or PBS only as a control, for 3 weeks. At 1, 2 and 4 weeks' post-administration, rats were sacrificed and fixed by transcardial perfusion with 4 % paraformaldehyde, following which tibiae were extracted for histochemical analysis. Compared with the control group, the number of tartrate-resistant acid phosphatase- and Cathepsin K-positive osteoclasts were significantly increased, and the expression of alkaline phosphatase in osteoblasts was decreased in trabecular bone of rats administered high-dose 1,25(OH)2D3, leading to decreased trabecular bone volume. In addition, the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) was increased, while that of osteoprotegerin was weaker in osteoblasts in the experimental group compared with the control group. Moreover, there was weaker immunoreactivity for EphrinB2 in osteoclasts and EphB4 in osteoblasts of trabecular bone in the experimental group compared with the control group. These findings suggest that long-term use of physiologically-high dose calcitriol may result in bone loss through RANKL/RANK/osteoprotegerin and EphrinB2-EphB4 signaling pathways, and that these negative effects could continue after drug withdrawal. Therefore, optimal limits for vitamin D administration need to be established for children and adolescents.
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, 250012, Jinan, China. liminqi@sdu.edu.cn.
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D056657:Cathepsin K / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism; D007150:Immunohistochemistry; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D036388:Ephrin-B2; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D036224:Receptor, EphB4; D000469:Alkaline Phosphatase; D056657:Cathepsin K; D002117:Calcitriol
keywords: 1,25(OH)2D3; Bone loss; EphrinB2–EphB4; Osteoclastogenesis; RANKL/RANK/OPG