A stable analogue of thromboxane A2, 9,11-epithio-11,12-methanothromboxane A2, stimulates bone resorption in vitro and osteoclast-like cell formation in mouse marrow culture.
Thromboxane A2 (TXA2) is a powerful promoter of platelet aggregation and smooth muscle contraction. However, this compound is highly unstable and is rapidly hydrated to a more stable metabolite, thromboxane B2 (TXB2). TXA2 has been considered to be involved in bone resorption, in particular bone loss caused by inflammatory diseases and by orthodontic treatment. However precise mechanisms of bone resorption caused by TXA2 have not yet been proved because of its highly unstable nature. Recently, a chemically stable analogue of TXA2, 9,11-epithio-11,12-methanothromboxane A2 (STA2), was successfully synthesized. Using this synthetic compound, we examined its in vitro bone resorbing activity and induction of osteoclast-like cells in a mouse marrow culture system in comparison with related compounds with bone resorbing activity. Like prostaglandin E2 (PGE2), a well-known bone resorbing agent, STA2 time- and dose-dependently stimulated the release of 45Ca from prelabelled mouse calvariae. Both STA2 and PGE2 induced the accumulation of cAMP in mouse calvariae. The TXA2 antagonist, ONO-3708, inhibited STA2-induced release of 45Ca. TXB2 induced neither bone resorption nor cAMP accumulation. When mouse marrow cells were cultured with STA2 for 8 days, osteoclast-like multinucleated cells appeared in parallel with the increase of the amount of STA2 added. Again TXB2 showed no effect on osteoclast-like cell formation. These results indicate a role for TXA2 in some form of bone resorption.
Saito
S
S
Department of Orthodontics, School of Dentistry, Showa University, Tokyo, Japan.
Yamasaki
K
K
Yamada
S
S
Matsumoto
A
A
Akatsu
T
T
Takahashi
N
N
Shibasaki
Y
Y
Suda
T
T
Fukuhara
T
T
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology*; D002132:Calcium Radioisotopes / Q000378:metabolism; D046508:Culture Techniques; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D013928:Thromboxane A2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013929:Thromboxane B2 / Q000494:pharmacology
D002132:Calcium Radioisotopes; D013929:Thromboxane B2; D013928:Thromboxane A2; C037866:STA 2; C049855:ONO 3708; D015232:Dinoprostone; D007213:Indomethacin