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Calcif Tissue Int ; 73(3): 265-73, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14667140

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.


Subject(s)
Calcitonin/pharmacology , Calcium Signaling/drug effects , Calcium , Cytosol/drug effects , Egtazic Acid/analogs & derivatives , Osteoclasts/drug effects , Surface-Active Agents/pharmacology , Animals , Animals, Newborn , Biotransformation , Bone Resorption , Calcitonin/metabolism , Calcium/metabolism , Calcium Signaling/physiology , Cell Line , Cell Movement/drug effects , Cell Movement/physiology , Cytosol/metabolism , Dose-Response Relationship, Drug , Egtazic Acid/pharmacology , Humans , Kidney/drug effects , Kidney/pathology , Kidney/physiology , Microscopy, Video , Osteoclasts/pathology , Osteoclasts/physiology , Rats , Rats, Wistar , Receptors, Calcitonin/genetics , Receptors, Calcitonin/metabolism , Surface-Active Agents/metabolism , Transfection
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