Up-regulation of bone morphogenetic protein receptor IB by growth factors enhances BMP-2-induced human bone cell functions.
Bone morphogenetic proteins (BMP) stimulate osteoblast differentiation by signal transduction via three BMP receptors (BMPR-IA, -IB, and -II). Several growth factors, including transforming growth factor-beta1 (TGF-beta1), fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-AB (PDGF-AB), have also been shown to play an important part in osteogenesis. The mechanism underlying these activities is unclear, but these growth factors could modulate the BMP/BMPR pathway by up-regulating BMPR expression, thereby enhancing the osteogenic responses of bone cells to the BMP. In this study we have therefore examined the effects of TGF-beta1, FGF-2, and PDGF-AB on BMPR expression and BMP-2-mediated osteoblast functions in primary human bone cells. The results showed that although the ligand BMP-2 and growth factors had little effect on BMPR-IA and -II transcript expression, they significantly up-regulated BMPR-IB mRNA specifically. However, only the growth factors, but not the ligand BMP-2, increased the surface expression of the BMPR-IB antigen, which was found to be due to a differential effect of BMP-2 and the growth factors on the Smurf1/Smad6-induced breakdown process. Pre-incubation of the cells with the growth factors significantly augmented BMP-2-induced Smad1/5/8 phosphorylation, and Dlx5 expression ALP activity, compared with that of cells treated with BMP-2 alone. When cells were transfected with siRNA targeting BMPR-IB, the growth factors neither up-regulated BMPR-IB transcript expression nor enhanced BMP-2-induced Smad1/5/8 phosphorylation, Dlx5 expression and ALP activity. The results indicate that increased BMPR-IB by TGF-beta1, FGF-2, and PDGF-AB significantly enhances BMP-2-induced osteogenic functions in vitro, suggesting that they might positively modulate bone formation by up-regulating BMPR-IB in vivo.
Singhatanadgit
Weerachai
W
Division of Biomaterials and Tissue Engineering, Eastman Dental Institute, University College London, 256 Gray's Inn Road, London, United Kingdom.
Salih
Vehid
V
Olsen
Irwin
I
D055396:Bone Morphogenetic Protein 2; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001842:Bone and Bones / Q000166:cytology*; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051905:Smad6 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C497802:SMAD6 protein, human; D051905:Smad6 Protein; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C095477:platelet-derived growth factor AB; D016222:Fibroblast Growth Factor 2; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D052005:Bone Morphogenetic Protein Receptors, Type I