Document Detail

Alendronate interacts with the inhibitory effect of 1,25(OH)2D3 on parathyroid hormone-related protein expression in human osteoblastic cells.
MedLine Citation:
PMID:  12510808     Owner:  NLM     Status:  MEDLINE    
The bisphosphonate alendronate is a potent inhibitor of bone resorption by its direct action on osteoclasts. In addition, there is some data suggesting that alendronate could also inhibit bone resorption indirectly by interacting with osteoblasts. Parathyroid hormone-related protein (PTHrP) produced by osteoblasts and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are regulators of bone remodeling, which have interrelated actions in these cells. In this study, we assessed whether alendronate can affect PTHrP expression in the presence or absence of 1,25(OH)2D3 in human primary osteoblastic (hOB) cells from trabecular bone. Cell total RNA was isolated, and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out using human PTHrP-specific primers. PTHrP in the hOB cell-conditioned medium was analyzed by a specific immunoradiometric assay. We found that PTHrP mRNA and secreted PTHrP were maximally inhibited by 10(-8) - 10(-6) M of 1,25(OH)2D3 treatment within 8-72 h in hOB cells. Alendronate (10(-14) - 10(-8) M) modified neither PTHrP mRNA nor PTHrP secretion, although it consistently abrogated the decrease in PTHrP production induced by 1,25(OH)2D3 in these cells. On the other hand, alendronate within the same dose range did not affect either the vitamin D receptor (VDR) mRNA or osteocalcin secretion, with or without 1,25(OH)2D3, in hOB cells. The inhibitory effect of alendronate on the 1,25(OH)2D3-induced decrease in PTHrP in these cells was mimicked by the calcium ionophore A23187 (5 x 10-6 M), while it was eliminated by 5 x 10(-5) M of nifedipine. Furthermore, although alendronate alone failed to affect [Ca2+]i in these cells, it stimulated [Ca2+]i after pretreatment of hOB cells with 10(-8) M of 1,25(OH)2D3, an effect that was abolished by 5 x 10(-5) M of nifedipine. These results show that alendronate disrupts the modulatory effect of 1,25(OH)2D3 on PTHrP production in hOB cells. Our findings indicate that an increase in calcium influx appears to be involved in the mechanism mediating this effect of alendronate.
L Gómez-García; P Esbrit; L Carreño; P Sabando; M García-Flores; M E Martinez
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  18     ISSN:  0884-0431     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2003-01-03     Completed Date:  2003-04-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  78-87     Citation Subset:  IM    
Research Division, Hospital La Paz, Madrid, Spain.
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MeSH Terms
Alendronate / administration & dosage*
Bone Resorption / genetics,  metabolism,  prevention & control
Calcitriol / administration & dosage*
Calcium Signaling
Cells, Cultured
Dose-Response Relationship, Drug
Drug Interactions
Gene Expression / drug effects
Osteoblasts / drug effects*,  metabolism*
Osteocalcin / biosynthesis
Parathyroid Hormone-Related Protein
Peptide Hormones / biosynthesis*,  genetics
RNA, Messenger / genetics,  metabolism
Receptors, Calcitriol / genetics
Reg. No./Substance:
0/PTHLH protein, human; 0/Parathyroid Hormone-Related Protein; 0/Peptide Hormones; 0/RNA, Messenger; 0/Receptors, Calcitriol; 104982-03-8/Osteocalcin; 32222-06-3/Calcitriol; 66376-36-1/Alendronate

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