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Eur J Pharmacol. 2008 Jan 28;579(1-3):40-9. Epub 2007 Oct 13.

Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts.


Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Osteoporosis is a reduction in skeletal mass due to an imbalance between bone resorption and bone formation.

Bone morphogenetic protein (BMP) plays important roles in osteoblastic differentiation and bone formation.

Therefore, components involved in BMP activation are good targets for the development of anti-osteoporosis drugs.

In this study, imperatorin and bergapten, two coumarin derivatives, were shown to enhance alkaline phosphatase (ALP) activity, type I collagen synthesis and bone nodule formation in primary cultured osteoblasts.

Imperatorin and bergapten increased mRNA levels of BMP-2 using quantitative RT-PCR, whereas the BMP-2 antagonist noggin attenuated the increase of ALP activity induced by imperatorin and bergapten, indicating that BMP-2 expression is required for the action of imperatorin and bergapten in osteoblastic maturation.

Both imperatorin and bergapten enhanced the phosphorylation of SMAD (transcription factors activated by TGF-beta) 1/5/8, p38 and extracellular signal-regulated protein (ERK).

Pretreatment of osteoblasts with p38 inhibitor (SB203580) or mitogen-activated protein kinase inhibitor (PD98059) or transfected with dominant negative mutant of p38 or ERK antagonized the elevation of BMP-2 expression and ALP activity induced by imperatorin and bergapten.

Local administration of imperatorin or bergapten into the metaphysis of the tibia via the implantation of a needle cannula significantly increased the BMP-2 immunostaining and bone volume of secondary spongiosa in tibia. Taken together, our results provide evidence that coumarin derivatives increase BMP-2 expression and enhance bone formation in rat via the p38 and ERK-dependent signaling pathway.

[PubMed - indexed for MEDLINE]

Pharmazie. 2004 Aug;59(8):643-5.

Coumarins from Cnidium monnieri (L.) and their proliferation stimulating activity on osteoblast-like UMR106 cells.


School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, P.R. China.

The proliferation of various fractions of alcoholic extracts from fruits of Cnidium monnieri (L.) Cuss (umbelifera) were screened using the osteoblast-like UMR106 cells in vitro.

The chloroform fraction from the crude extract was found to have the most stimulating activity.

Three coumarins (osthole, bergapten and imperatorin) were isolated from this fraction by activity-guided assay, and their effects on osteoblastic proliferation were investigated.

Osthole, a major pharmacologically active constituent, significantly promoted the cells' activity.

Bergapten and imperatorin were less effective than osthole.

These results suggested Cnidium monnieri (L.) Cuss extracts might have potential activity against osteoporosis, and its chloroform fraction might contain active constituents stimulating osteoblasts.

[PubMed - indexed for MEDLINE]

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