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4C,D). FAM-RIS, ROX-RIS, and AF647-RIS also showed differences in mineral surface penetration when administered together, with the ROX conjugate showing decreased surface penetration and the AF647 conjugate slightly increased penetration, relative to FAM-RIS (Fig. 4E,F). These findings are consistent with the differences in mineral affinity of these compounds in vitro, showing ROX-labeled compounds to have a higher mineral affinity than FAM- and AF647-labeled compounds (Fig. 1). Similar differences in surface penetration http://www.selleck.cn/products/Bortezomib.html were observed in trabecular bone, with the low-affinity AF647-3-PEHPC again penetrating farthest into the bone matrix at sites of bone formation (Fig. 4G). Furthermore, analysis of the tibia of a mouse treated with AF647-RIS, FAM-3-PEHPC, and xylenol orange showed xylenol orange (even lower bone affinity than the 3-PEHPC conjugates) to penetrate farthest, whereas AF647-RIS showed the most superficial labeling (Fig. 4H). Moreover, when dentine discs from elephant tusk, a relatively poorly mineralized tissue, were labeled with fluorescent BP analogues in vitro, a similar pattern of mineral penetration was observed, with FAM-3-PEHPC penetrating further into the dentine surface compared to AF647-RIS, which in turn showed similar surface penetration to FAM-RIS (Supplemental Fig. S3). In contrast, no clear differences in penetration between high- and low-affinity compounds were observed at quiescent bone surfaces, and the seams of fluorescence at these areas were much thinner (Fig. 4I). Evidence of differential penetration was found at http://www.selleckchem.com/products/PD-0332991.html areas of resorption, although this was less pronounced than at forming surfaces (Fig. 3A). We previously reported the binding of fluorescent RIS analogues, FAM-RIS and AF647-RIS, to the walls of osteocyte lacunae and within the canaliculi extending from the vascular channels or bone surface to the osteocyte lacunae.17 In the current study, it was consistently observed, both in rats (Fig. 5) and in mice (Supplemental http://www.selleckchem.com/products/Everolimus(RAD001).html Fig. S4), that the lower-affinity compounds (fluorescent analogues of dRIS and 3-PEHPC, and xylenol orange) showed increased labeling of osteocyte lacunar walls, as well as canaliculi extending from the bone surface or vascular channels, compared with the high-affinity fluorescent analogues of RIS. Quantification of osteocyte lacunar labeling relative to vascular channel labeling confirmed that the degree of penetration into the osteocyte network was significantly different between the fluorescent RIS, dRIS, and 3-PEHPC analogues (Fig. 5B,C; p?