Localization of Minodronate in Mouse Femora Through Isotope Microscopy.
Minodronate is highlighted for its marked and sustained effects on osteoporotic bones. To determine the duration of minodronate's effects, we have assessed the localization of the drug in mouse bones through isotope microscopy, after labeling it with a stable nitrogen isotope ([(15)N]-minodronate). In addition, minodronate-treated bones were assessed by histochemistry and transmission electron microscopy (TEM). Eight-week-old male ICR mice received [(15)N]-minodronate (1 mg/kg) intravenously and were sacrificed after 3 hr, 24 hr, 1 week, and 1 month. Isotope microscopy showed that [(15)N]-minodronate was present mainly beneath osteoblasts rather than nearby osteoclasts. At 3 hr after minodronate administration, histochemistry and TEM showed osteoclasts with well-developed ruffled borders. However, osteoclasts were roughly attached to the bone surfaces and did not feature ruffled borders at 24 hr after minodronate administration. The numbers of tartrate-resistant acid phosphatase-positive osteoclasts and alkaline phosphatase-reactive osteoblastic area were not reduced suddenly, and apoptotic osteoclasts appeared in 1 week and 1 month after the injections. Von Kossa staining demonstrated that osteoclasts treated with minodronate did not incorporate mineralized bone matrix. Taken together, minodronate accumulates in bone underneath osteoblasts rather than under bone-resorbing osteoclasts; therefore, it is likely that the minodronate-coated bone matrix is resistant to osteoclastic resorption, which results in a long-lasting and bone-preserving effect.
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Hiromi
H
Hongo
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Muneteru
M
Sasaki
Hokkaido University, Sapporo, JapanNatural History Sciences, Isotope Imaging Laboratory, Creative Research Institution (SK, HY) Hokkaido University, Sapporo, Japan
Sachio
S
Kobayashi
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Tomoka
T
Hasegawa
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Tomomaya
T
Yamamoto
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Kanako
K
Tsuboi
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Erika
E
Tsuchiya
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Tomoya
T
Nagai
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Naznin
N
Khadiza
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Miki
M
Abe
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Ai
A
Kudo
Division of Biochemistry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan (KO)
Kimimitsu
K
Oda
Dental School, Federal University of Sergipe, Aracaju, Brazil (PHLF)
Paulo
P
Henrique Luiz de Freitas
Shandong Provincial Key Laboratory of Oral Biomedicine, School of Stomatology, Shandong University, Jinan, China (ML)
Minqi
M
Li
Hokkaido University, Sapporo, JapanNatural History Sciences, Isotope Imaging Laboratory, Creative Research Institution (SK, HY) Hokkaido University, Sapporo, Japan
Hisayoshi
H
Yurimoto
Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine (HH, MS, TH, TY, KT, ET, TN, NK, MA, AK, NA) Hokkaido University, Sapporo, Japan
Norio
N
Amizuka
D000818:Animals; D050071:Bone Density Conservation Agents / Q000032:analysis*; D002247:Carbon Isotopes; D002452:Cell Count; D004164:Diphosphonates / Q000032:analysis*; D005269:Femur / Q000737:chemistry* / Q000166:cytology; D007093:Imidazoles / Q000032:analysis*; D008297:Male; D008813:Mice, Inbred ICR; D008853:Microscopy / Q000379:methods; D009587:Nitrogen Isotopes; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology
D050071:Bone Density Conservation Agents; D002247:Carbon Isotopes; D004164:Diphosphonates; D007093:Imidazoles; D009587:Nitrogen Isotopes; C087958:YM 529
bisphosphonate; isotope microscopy; minodronate; osteoblast; osteoclast
Endocrinology. 2003 Dec;144(12):5441-9
14500574
Endocrine. 2013 Aug;44(1):237-46
23099796
Biochim Biophys Acta. 1976 Dec 21;451(2):549-59
826271
Calcif Tissue Int. 2015 Jul;97(1):23-31
25926046
J Cell Sci. 1997 Aug;110 ( Pt 15):1767-80
9264464
Bone. 2011 Jul;49(1):20-33
21497677
J Bone Miner Res. 2011 Mar;26(3):503-11
20814967
N Engl J Med. 2003 Sep 25;349(13):1207-15
14500804
Micron. 2005;36(7-8):688-95
16182547
J Bone Miner Res. 1994 Nov;9(11):1777-87
7863829
J Electron Microsc (Tokyo). 2009 Apr;58(2):55-65
19225034
New Phytol. 2014 Apr;202(2):594-605
24494717
Calcif Tissue Int. 2002 Jan;70(1):40-7
11907706
Curr Pharm Des. 2003;9(32):2643-58
14529538
Lancet. 2013 Jul 6;382(9886):50-6
23683600
J Lipid Res. 1992 Nov;33(11):1657-63
1464749
Eur J Endocrinol. 2012 Apr;166(4):735-41
22258112
J Bone Miner Res. 1987 Dec;2(6):595-610
3455637
Nucleic Acids Res. 2013 Jul;41(12):e126
23632164
Bone. 2013 Nov;57(1):206-19
23954506
Calcif Tissue Res. 1970;6(3):183-96
5500673
Endocrinology. 2016 Jul;157(7):2604-20
27227535
J Pharmacol Exp Ther. 2001 Feb;296(2):235-42
11160603
Bone. 2013 May;54(1):1-7
23356990
Calcif Tissue Res. 1969;3(2):151-62
5769901
J Biochem. 1999 Oct;126(4):694-9
10502677
Bone. 2014 Jul;64:88-94
24727162
Bone. 2001 May;28(5):524-31
11344052
Nature. 2004 Apr 29;428(6986):921-4
15118720
J Bone Miner Res. 1995 Oct;10(10):1478-87
8686503
J Bone Miner Res. 1999 Nov;14(11):1855-60
10571685
J Bone Miner Res. 1998 Apr;13(4):581-9
9556058
Bone. 2006 Nov;39(5):1053-8
16807159
Bone. 2009 Jun;44(6):1078-84
19264155
Calcif Tissue Res. 1969;3(3):211-37
4894738
Mol Pharmacol. 1996 Nov;50(5):1127-38
8913344
Bone. 2013 Mar;53(1):277-83
23207800
Osteoporos Int. 2009 Aug;20(8):1429-37
19101754
Calcif Tissue Int. 2014 Aug;95(2):166-73
24903232
J Bone Miner Metab. 2012 Jul;30(4):439-46
22134624
J Bone Miner Res. 2009 Sep;24(9):1586-97
19419301
J Bone Miner Metab. 2001;19(5):267-76
11498728
J Clin Invest. 1991 Dec;88(6):2095-105
1661297