Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2012) 29 P142

ICEECE2012 Poster Presentations Bone & Osteoporosis (67 abstracts)

BMP-3b inhibits osteoblast differentiation via Smad2/3 pathway by counteracting Smad1/5/8 signaling

F. Otsuka 1 , J. Hino 2 , Y. Matsumoto 1 , T. Miyoshi 1 , M. Takano 1 , M. Miyazato 2 , H. Makino 1 & K. Kangawa 2


1Okayama University Graduate School, Okayama, Japan; 2National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.


Involvement of BMP-3b (also called GDF-10) in osteogenesis, embryogenesis and adipogenesis has been reported to date. However, the functional receptors and intracellular signaling of BMP-3b have yet to be determined. In the present study, we studied the cellular mechanism of BMP-3b in osteoblast differentiation using mouse myoblastic C2C12 cells, which show osteoblasitc differentiation in response to osteogenetic BMP ligands. BMP-3b stimulated activin/TGF-β-responsive promoter activities. In contrast, the stimulatory actions of BMP-3b on activin/TGF-β-responsive activities were suppressed by co-treatment with BMP-2. BMP-responsive promoter activities stimulated by BMP-2 were significantly inhibited by treatment with BMP-3b. BMP-3b suppressed the expression of osteoblastic markers including Runx2, osteocalcin and type-1 collagen induced by BMP-2, -4, -6 and -7. BMP-2-induced Smad1/5/8 phosphorylation and mRNA levels of the BMP target gene Id-1 were also suppressed by co-treatment with BMP-3b, although BMP-3b failed to activate Smad1/5/8 signaling. Of interest, the BMP-3b suppression of BMP-2-induced Id-1 expression was not observed in cells overexpressing co-Smad4 molecules. On the other hand, BMP-3b directly activated Smad2/3 phosphorylation and activin/TGF-β target gene PAI-1 mRNA expression, while BMP-2 suppressed BMP-3b-induced Smad2/3 signal activation. BMP-2 inhibition of BMP-3b-induced PAI-1 expression was also reversed by overexpression of Smad4. Experiments using inhibitors (dorsomorphin and LDN-193189) for BMP-Smad1/5/8 pathways demonstrated that these BMP-3b effects were mediated via receptors other than ALK-2, -3 and -6. Furthermore, results of inhibitory studies using extracellular domains for BMP receptor constructs showed that the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. Collectively, BMP-3b plays an inhibitory role in the process of osteoblast differentiation, in which BMP-3b and BMP-2 are mutually antagonistic possibly by competing with the availability of Smad4.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Volume 29

15th International & 14th European Congress of Endocrinology

European Society of Endocrinology 

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