Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778

Citation
K. Notoya et al., Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778, J PHARM EXP, 290(3), 1999, pp. 1054-1064
Citations number
42
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
00223565 → ACNP
Volume
290
Issue
3
Year of publication
1999
Pages
1054 - 1064
Database
ISI
SICI code
0022-3565(199909)290:3<1054:EOOIVA>2.0.ZU;2-O
Abstract
TAK-778 [(2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)- 1,2,4,5-tetrahyd ro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin -2-carboxyamide; mw 505 .53], a novel osteoblast differentiation promoting compound, was characteri zed in vitro and in vivo models. TAK-778 at doses of 10(-6) M and higher pr omoted potently bone-like nodule formation in the presence of dexamethasone in rat bone marrow stromal cell culture. This was accompanied by increases in cellular alkaline phosphatase activity, soluble collagen release, and o steocalcin secretion. Under the culture conditions, TAK-778 also stimulated the secretion of transforming growth factor-p and insulin-like growth fact or-I, indicating that TAK-778 may exert regulatory effects on osteoblast di fferentiation via autocrine/paracrine mechanisms. Furthermore, the in vivo osteogenic potential of TAK-778 was studied in bony defect and osteotomy an imal models, using sustained release microcapsules consisted of a biodegrad able polymer, poly (dl-lactic/glycolic) acid (PLGA). Single local injection of TAK-778/PLGA-microcapsules (PLGA-MC) (0.2-5 mg/site) to rat skull defec ts resulted in a dose-dependent increase in new bone area within the defect s after 4 weeks. When the pellet containing TAK-778/PLGA-MC (4 mg/pellet) w as packed into place to fill the tibial segmental defect in rabbit, this pe llet induced osseous union within 2 months, whereas the placebo pellet did not. In addition, single local application of TAK-778/PLGA-MC (10 mg/site) to rabbit tibial osteotomy site enhanced callus formation accompanied by an increase in breaking force after 30 days. These results reveal for the fir st time that a nonendogenous chemical compound promotes potently osteogenes is in vitro and enhances new bone formation during skeletal regeneration an d bone repair in vivo and should be useful for the stimulation of fracture healing.