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Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts.
Eur J Pharmacol. 2008 Jan 28; 579(1-3):40-9.EJ

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17980360

Citation

Tang, Chih-Hsin, et al. "Enhancement of Bone Morphogenetic Protein-2 Expression and Bone Formation By Coumarin Derivatives Via P38 and ERK-dependent Pathway in Osteoblasts." European Journal of Pharmacology, vol. 579, no. 1-3, 2008, pp. 40-9.
Tang CH, Yang RS, Chien MY, et al. Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts. Eur J Pharmacol. 2008;579(1-3):40-9.
Tang, C. H., Yang, R. S., Chien, M. Y., Chen, C. C., & Fu, W. M. (2008). Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts. European Journal of Pharmacology, 579(1-3), 40-9.
Tang CH, et al. Enhancement of Bone Morphogenetic Protein-2 Expression and Bone Formation By Coumarin Derivatives Via P38 and ERK-dependent Pathway in Osteoblasts. Eur J Pharmacol. 2008 Jan 28;579(1-3):40-9. PubMed PMID: 17980360.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancement of bone morphogenetic protein-2 expression and bone formation by coumarin derivatives via p38 and ERK-dependent pathway in osteoblasts. AU - Tang,Chih-Hsin, AU - Yang,Rong-Sen, AU - Chien,Mei-Yin, AU - Chen,Chien-Chich, AU - Fu,Wen-Mei, Y1 - 2007/10/13/ PY - 2007/04/27/received PY - 2007/07/30/revised PY - 2007/10/04/accepted PY - 2007/11/6/pubmed PY - 2008/4/16/medline PY - 2007/11/6/entrez SP - 40 EP - 9 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 579 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17980360/Enhancement_of_bone_morphogenetic_protein_2_expression_and_bone_formation_by_coumarin_derivatives_via_p38_and_ERK_dependent_pathway_in_osteoblasts_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)01108-9 DB - PRIME DP - Unbound Medicine ER -