Abstract:
:The peptide hormone calcitonin is a potent inhibitor of osteoclastic resorption, but it is unstable and poorly absorbed following oral administration. Conjugates of salmon calcitonin covalently linked to low-molecular-weight amphiphilic polymers show improved stability and absorption. The purpose of this study was to investigate the biological activity of these conjugates in vitro using rat osteoclasts and HEK-293 cells transfected with the C1a isoform of the calcitonin receptor. Salmon calcitonin or its conjugates (10 pM-10 nM) caused rapid arrest of osteoclast membrane ruffling and subsequent retraction. The same amphiphilic polymer attached to an unrelated protein had no effect on osteoclast morphology or motility. Since calcitonin-induced retraction of osteoclasts is thought to be mediated by Ca2+ signaling, we investigated the effects of calcitonin and its conjugates on cytosolic free Ca2+ concentration ([Ca24]i). In HEK-293 cells transfected with the calcitonin receptor, these agents induced transient elevations of [Ca2+]i. However, the rise of [Ca2+]i in HEK-293 cells occurred at concentrations 100-1000-fold higher than those required to elicit osteoclast retraction. To investigate the role of Ca2+ in osteoclast retraction, we preloaded cells with BAPTA to buffer changes in [Ca2+]i. BAPTA decreased the initial rate of calcitonin-induced osteoclast retraction, but it did not affect the degree of retraction 2-3 hours following calcitonin, indicating that retraction is mediated primarily by Ca(2+)-independent processes. We conclude that calcitonin conjugates cause osteoclast retraction and [Ca2+]i signaling in a manner similar to that elicited by calcitonin. Thus, orally bioavailable calcitonin conjugates show potential for use as antiresorptive agents.
journal_name
Calcif Tissue Intjournal_title
Calcified tissue internationalauthors
Komarova SV,Shum JB,Paige LA,Sims SM,Dixon SJdoi
10.1007/s00223-002-1051-4subject
Has Abstractpub_date
2003-09-01 00:00:00pages
265-73issue
3eissn
0171-967Xissn
1432-0827journal_volume
73pub_type
杂志文章abstract::The purpose of this study was to use the concept of metastable equilibrium solubility (MES) to describe the anomalous solubility behavior of carbonated apatite (CAP) in the presence of solution strontium. A CAP sample (4.8 wt% CO(3), synthesized at 70 degrees C) was prepared by precipitation. Baseline MES distribution...
journal_title:Calcified tissue international
pub_type: 杂志文章
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journal_title:Calcified tissue international
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journal_title:Calcified tissue international
pub_type: 杂志文章
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journal_title:Calcified tissue international
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journal_title:Calcified tissue international
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journal_title:Calcified tissue international
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journal_title:Calcified tissue international
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Calcified tissue international
pub_type: 杂志文章
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journal_title:Calcified tissue international
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::The absorption kinetics of intranasal salmon calcitonin were assessed in 4 normal subjects and 9 patients with Klinefelter's syndrome. After administration, absorption occurred within 5 minutes. There was a highly significant correlation between the amount administered and the amount absorbed (r = -0.83, P less than 0...
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