Roelofs AJ, Coxon FP, Ebetino FH, Lundy MW, Henneman ZJ, Nancollas GH, Sun S, Blazewska KM, Lynn F Bala J, Kashemirov BA, Khalid AB, McKenna CE, Rogers MJ
Fluorescent Risedronate Analogs Reveal Bisphosphonate Uptake by Bone Marrow Monocytes and Localization Around Osteocytes In Vivo. [JOURNAL ARTICLE]
J Bone Miner Res 2009 Oct 12.
Abstract Bisphosphonates are effective anti-resorptive agents due to their bone-targeting property and ability to inhibit osteoclasts by preventing protein prenylation. It remains unclear, however, whether any non-osteoclast cells are directly affected by these drugs in vivo. Two fluorescent risedronate analogs, 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 three-month old mice, fluorescent risedronate analogs were bound to bone surfaces. More detailed analysis revealed labeling of vascular channel walls within cortical bone. Furthermore, fluorescent risedronate analogs 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 analog FAM-RIS caused accumulation of unprenylated Rap1A in these cells. In addition, CD14(high) 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 analogs 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, BPs may exert direct effects on bone marrow monocytes in vivo.
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