Anabolic action of parathyroid hormone is skeletal site specific at the tissue and cellular levels in mice.
The cellular and molecular events triggering the anabolic response of the skeleton to exogenous parathyroid hormone (PTH) are not well understood. Despite the numerous bone mass studies in rats, few data are available for mice. Therefore, we treated 10-week-old female intact C57BL/6J mice with human PTH(1-34) delivered subcutaneously at a dose of 40 microg/kg per day 5 days a week for 3 weeks and 7 weeks. Bone mineral density (BMD) of total bone, femur, tibia, and lumbar vertebrae was measured weekly by PIXImus. Bone turnover was examined by histomorphometry, and gene expression of bone formation and resorption markers and osteoclastogenesis regulators in the excised femur and tibia was assessed by reverse-transcription polymerase chain reaction (RT-PCR) at 3 weeks and 7 weeks. The PTH-stimulated increase in BMD was more prominent in the tibia and femur than in the lumbar vertebrae, with an anabolic effect detected within 1-2 weeks and BMD continuing to increase. The appearance of a detectable PTH-stimulated increase in BMD was slower in the lumbar vertebrae where the increase was only significant after 7 weeks of treatment. Histomorphometric analysis of the proximal tibia at both 3 weeks and 7 weeks indicated significant time-dependent increases in trabecular area, trabecular number, trabecular and cortical widths, and osteoblast and osteoid perimeters. In the lumbar vertebrae, these stimulatory effects of PTH on trabecular area, trabecular number, and cortical width were smaller and not detected until 7 weeks. PTH-stimulated increases in bone turnover were evident by increased gene expression of osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), and receptor of activator nuclear factor kappaB (NF-kappaB) ligand (RANKL) in the tibia and femur. No significant difference in gene expression was observed between the two long bone sites. In conclusion, PTH exerts an anabolic action at the tissue and cellular levels in intact mice and the magnitude and temporal pattern of this anabolic action, as assessed by densitometry and histomorphometry, are skeletal site specific.
Iida-Klein
Akiko
A
Regional Bone Center, Helen Hayes Hospital, New York State Department of Health, West Haverstraw 10993-1195, USA.
Zhou
Hua
H
Lu
Shi Shou
SS
Levine
Lance R
LR
Ducayen-Knowles
Mercedes
M
Dempster
David W
DW
Nieves
Jeri
J
Lindsay
Robert
R
D000135:Acid Phosphatase / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005269:Femur / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000235:genetics; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D002352:Carrier Proteins; D006023:Glycoproteins; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018003:Receptors, Calcitonin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase