Exogenous 1,25-dihydroxyvitamin D3 exerts a skeletal anabolic effect and improves mineral ion homeostasis in mice that are homozygous for both the 1alpha-hydroxylase and parathyroid hormone null alleles.
1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and PTH each modulate calcium and skeletal homeostasis. To identify 1,25(OH)(2)D(3)-mediated skeletal and mineral ion actions independent of PTH, double-knockout mice, which are homozygous for both the 1alpha-hydroxylase and PTH null alleles, were treated with 1,25(OH)(2)D(3), sc, from d 4 to 14 and compared with vehicle-treated animals. Serum calcium rose in 1,25(OH)(2)D(3)-treated double-knockout mice, and messenger RNA and protein levels of the renal calcium transporters TRPV5, calbindin-D(28K), calbindin-D(9K), and Na(+)/Ca(2+) exchanger 1 were up-regulated. Parameters of endochondral bone formation, including long bone length, epiphyseal volume, chondrocyte proliferation and differentiation, and cartilage matrix mineralization, were all increased by 1,25(OH)(2)D(3), Exogenous 1,25(OH)(2)D(3) also increased both trabecular and cortical bone; augmented both osteoblast number and type I collagen deposition in bone matrix; and up-regulated expression levels of the osteoblastic genes alkaline phosphatase, type I collagen, and osteocalcin. Furthermore, in 1,25(OH)(2)D(3)-treated double mutants, osteoclastic bone resorption appeared to decline. The results indicate that administered 1,25(OH)(2)D(3) used intestinal and renal but not skeletal mechanisms to elevate serum calcium and that this sterol can promote endochondral and appositional bone increases independent of endogenous PTH.
Xue
Yingben
Y
The Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology and Institute of Dental Research, Nanjing Medical University, Nanjing, Jiangsu 210029, The People's Republic of China.
Karaplis
Andrew C
AC
Hendy
Geoffrey N
GN
Goltzman
David
D
Miao
Dengshun
D
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics* / Q000502:physiology; D000135:Acid Phosphatase / Q000378:metabolism; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001846:Bone Development / Q000187:drug effects*; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects; D010281:Parathyroid Hormone / Q000235:genetics* / Q000502:physiology; D010758:Phosphorus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D014057:Tomography, X-Ray Computed
D007527:Isoenzymes; D008903:Minerals; D010281:Parathyroid Hormone; D010758:Phosphorus; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002117:Calcitriol; D002118:Calcium