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Fluorescent Risedronate Analogues Reveal Bisphosphonate Uptake by Bone Marrow Monocytes and Localization Around Osteocytes In Vivo
Authors
Anke J Roelofs
Aysha B Khalid
+49 more
Azuma
Bonneville
Boris A Kashemirov
Charles E McKenna
Coxon
Coxon
Coxon
Dunford
Fisher
Follet
Frank H Ebetino
Fraser P Coxon
George H Nancollas
Giraudo
Gober
Henneman
Hewitt
Hughes
Joy Lynn F Bala
Kashemirov
Katarzyna M Blazewska
Kavanagh
Kozloff
Kunzmann
LeGeros
Lin
Luckman
Löwik
Mantovani
Mark W Lundy
Masarachia
Melani
Michael J Rogers
Nancollas
Plotkin
Plotkin
Plotkin
Roelofs
Roelofs
Roelofs
Russell
Sato
Shuting Sun
Thompson
Thompson
Van Beek
Yamagishi
Zachary J Henneman
Zaheer
Publication date
Publisher
Wiley Subscription Services, Inc., A Wiley Company
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PubMed
Abstract
Bisphosphonates are effective antiresorptive agents owing to their bone-targeting property and ability to inhibit osteoclasts. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogues, carboxyfluorescein-labeled risedronate (FAM-RIS) and Alexa Fluor 647–labeled risedronate (AF647-RIS), were used to address this question. Twenty-four hours after injection into 3-month-old mice, fluorescent risedronate analogues were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogues were present in osteocytic lacunae in close proximity to vascular channels and localized to the lacunae of newly embedded osteocytes close to the bone surface. Following injection into newborn rabbits, intracellular uptake of fluorescently labeled risedronate was detected in osteoclasts, and the active analogue FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14high bone marrow monocytes showed relatively high levels of uptake of fluorescently labeled risedronate, which correlated with selective accumulation of unprenylated Rap1A in CD14+ cells, as well as osteoclasts, following treatment with risedronate in vivo. Similar results were obtained when either rabbit or human bone marrow cells were treated with fluorescent risedronate analogues in vitro. These findings suggest that the capacity of different cell types to endocytose bisphosphonate is a major determinant for the degree of cellular drug uptake in vitro as well as in vivo. In conclusion, this study shows that in addition to bone-resorbing osteoclasts, bisphosphonates may exert direct effects on bone marrow monocytes in vivo. © 2010 American Society for Bone and Mineral Researc
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Last time updated on 03/01/2020