Document Detail

Enhancement of osteogenesis in vitro and in vivo by a novel osteoblast differentiation promoting compound, TAK-778.
MedLine Citation:
PMID:  10454478     Owner:  NLM     Status:  MEDLINE    
TAK-778 [(2R,4S)-(-)-N-(4-diethoxyphosphorylmethylphenyl)-1,2,4, 5-tetrahydro-4-methyl-7, 8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxyamide; mw 505.53], a novel osteoblast differentiation promoting compound, was characterized in vitro and in vivo models. TAK-778 at doses of 10(-6) M and higher promoted 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 osteocalcin secretion. Under the culture conditions, TAK-778 also stimulated the secretion of transforming growth factor-beta and insulin-like growth factor-I, indicating that TAK-778 may exert regulatory effects on osteoblast differentiation via autocrine/paracrine mechanisms. Furthermore, the in vivo osteogenic potential of TAK-778 was studied in bony defect and osteotomy animal models, using sustained release microcapsules consisted of a biodegradable 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 defects resulted in a dose-dependent increase in new bone area within the defects after 4 weeks. When the pellet containing TAK-778/PLGA-MC (4 mg/pellet) was packed into place to fill the tibial segmental defect in rabbit, this pellet 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 first time that a nonendogenous chemical compound promotes potently osteogenesis in vitro and enhances new bone formation during skeletal regeneration and bone repair in vivo and should be useful for the stimulation of fracture healing.
K Notoya; H Nagai; T Oda; M Gotoh; T Hoshino; H Muranishi; S Taketomi; T Sohda; H Makino
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  290     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1999 Sep 
Date Detail:
Created Date:  1999-09-21     Completed Date:  1999-09-21     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1054-64     Citation Subset:  IM; S    
Pharmaceutical Research Laboratories IV, Takeda Chemical Industries, Ltd., Drug Safety Research Laboratories, Pharmaceutical Development Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
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MeSH Terms
Benzothiepins / administration & dosage,  pharmacology*
Biocompatible Materials / administration & dosage
Bone Marrow Cells / cytology,  drug effects
Bone Regeneration / drug effects
Cell Differentiation / drug effects
Cells, Cultured
Lactic Acid / administration & dosage
Mice, Inbred C3H
Osteoblasts / cytology*,  drug effects*,  enzymology
Osteogenesis / drug effects*
Polyglycolic Acid / administration & dosage
Polymers / administration & dosage
Rats, Sprague-Dawley
Skull / drug effects,  injuries
Stromal Cells / cytology,  drug effects
Tibial Fractures / drug therapy
Reg. No./Substance:
0/Benzothiepins; 0/Biocompatible Materials; 0/Polymers; 0/TAK 778; 0/polylactic acid-polyglycolic acid copolymer; 26009-03-0/Polyglycolic Acid; 50-21-5/Lactic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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