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Title: Expression and regulation of bone morphogenetic protein receptors in human alveolar bone cells
Author: Singhatanadgit, Weerachai
ISNI:       0000 0004 2672 5800
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2007
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Bone morphogenetic proteins (BMPs) are members of the transforming growth factor P (TGF-P) superfamily of growth factors that stimulate osteoblast differentiation and function. They exert their biological activities through signal transduction via three specific serine/threonine kinase transmembrane receptors, designated types-IA, -IB and -II (BMPR-IA, -IB and -II). These BMP-specific receptors thus determine in part the sensitivity and responsiveness of target cells to the BMP and thereby the biological activity of the BMP. However, little is known about BMPR-IA, -IB and -II in bone. The present study was therefore carried out to examine the expression and regulation of the BMPR in primary human alveolar bone (AB) cells in vitro. Cells were obtained from explants of human AB and exhibited a number of characteristic phenotypic features of osteoblasts. They were also found to express all three BMPR mRNA transcripts and proteins, each of which had a unique subcellular distribution. For example, in addition to its expected localisation at the plasma membrane, a major proportion of BMPR-IB was also observed in the cytoplasm and the nucleus. Moreover, the distribution of BMPR-IB was found to be highly regulated by TGF-pi, which caused a pronounced translocation of this receptor to the plasma membrane, resulting in a marked increase in BMP-2 binding and bone cell response. The BMPR also appeared to be differentially controlled at the post-translational level by inflammatory cytokines, which were shown, for the first time, to cause shedding of the cell surface proteins and the concurrent generation of 'soluble' forms of the BMPR. IL-1 p and TNF-ct were found to significantly induce the shedding of soluble BMPR-IB specifically, thereby reducing BMPR-IB surface expression and diminishing BMP-2- induced AB cell functions, such as Smad 1/5/8 phosphorylation, alkaline phosphatase (ALP) activity and osteocalcin (OC) expression. In contrast, the expression of BMPR-IB was found to be up-regulated by osteogenic growth factors including TGF-pl, FGF-2 and PDGF-AB, which enhanced BMP-2-induced AB cell functions. The biological importance of BMPR-IB in these cells was established using an RNA interference approach, which demonstrated that the expression of pivotal osteoblast-associated genes ALP, OC, distal-less homeobox 5 (Dlx5) and core binding factor alpha1 (Cbfalpha1) was dependent on the BMPR-IB signalling pathway. In conclusion, the activities of the BMPR-IA, -IB and -II genes in primary human AB cells were found to be controlled by a number of biological mediators. In addition, the expression of these receptors was also regulated at both the transcriptional and post- translational levels, with BMPR-IB being the most responsive receptor, at least in vitro. These findings suggest that BMPR-IB could thus be a possible therapeutic target for eliciting improved BMP-induced bone healing in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available