1 alpha,25-Dihydroxyvitamin D3[1 alpha,25-(OH)2D3]-26,23-lactone inhibits 1,25-(OH)2D3-mediated fusion of mouse bone marrow mononuclear cells.
Vitamin D3 and its hormonally active metabolite 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] can be metabolized to a number of daughter metabolites, including 1 alpha,25-(OH)2D3-26,23-lactone; this latter compound has four diastereoisomers. The 23(S),25(R)-lactone (naturally occurring) and the 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactone are both known to be able to inhibit bone resorption induced by 1 alpha,25-(OH)2D3 under in vivo or in vitro conditions. To understand the mechanism of the inhibitory action of these two isomers on bone resorption we investigated the effects of 1 alpha,25-(OH)2D3-26,23-lactone on unfractionated mouse bone marrow cells in vitro. The addition of 1 alpha,25-(OH)2D3 to these cultures dose-dependently stimulated the formation of multinucleated cells over a range of 10(-9) - 10(-7) M. The 23(S),25(S)- and 23(R),25(R)-1 alpha,25-(OH)2D3-26,23-lactones also increased the number of multinucleated cells, whereas the 23(S),25(R)- and 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactones failed to do so. In addition, these latter two diastereomers inhibited the 1 alpha,25-(OH)2D3 stimulation of multinucleated cell formation, although the 23(S),25(S)- and 23(R),25(R)-1 alpha,25-(OH)2D3-26,23-lactones and 24R,25-(OH)2D3 did not. These multinucleated cells responded to calcitonin and contained tartrate-resistant acid phosphatase, both of which are characteristic of osteoclasts. The present data suggest that inhibition of multinucleated cell formation is the mechanism by which the 23(S),25(R)- or 23(R),25(S)-1 alpha,25-(OH)2D3-26,23-lactone inhibits bone resorption induced by 1 alpha,25-(OH)2D3.
Ishizuka
S
S
Department of Biochemistry, Teijin Institute for Bio-Medical Research, Tokyo, Japan.
Kurihara
N
N
Hakeda
S
S
Maeda
N
N
Ikeda
K
K
Kumegawa
M
M
Norman
A W
AW
D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000187:drug effects*; D002116:Calcitonin / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002452:Cell Count; D002454:Cell Differentiation; D002467:Cell Nucleus; D002478:Cells, Cultured; D051379:Mice; D008813:Mice, Inbred ICR; D010010:Osteoclasts / Q000187:drug effects / Q000648:ultrastructure; D013237:Stereoisomerism; D013644:Tartrates / Q000494:pharmacology
D013644:Tartrates; C026947:1,25-dihydroxyvitamin D3-26,23-lactone; D002116:Calcitonin; D000135:Acid Phosphatase; D002117:Calcitriol; C029768:tartaric acid