Function of cells producing type I collagen: potential
influence of the vasculature.
Doctoral thesis, UCL (University College London).
The interplay of fundamental extracellular factors involved in the control of cells producing type I collagen is still not fully understood. Bone formation by osteoblasts is known to be dependent on a good vascular supply and to be inhibited by hypoxia. This strongly suggests that oxygen carried by the blood acts as a key regulator of connective tissue cell function. To investigate further the role played by vascular oxygen supply in connective tissues, calvarial osteoblasts and dermal fibroblasts were grown under hypoxic (2% oxygen) and normoxic conditions (20% oxygen). Hypoxia caused striking decreases in growth and collagen formation by both cell types, along with increased expression of VEGF mRNA by fibroblasts. A novel assay using osteoblasts isolated from neonatal rat long bones was developed to examine more closely the bone formation process. These osteoblasts were characterised alongside autologous calvarial cells. In vivo, limb bones and flat bones form by distinct developmental processes; unexpectedly, osteoblasts from both sources behaved similarly in culture, with no clear differences in growth, gene expression or bone formation. As part of the characterisation of the long-bone-derived osteoblasts, the direct effects of PTH were examined. The mechanism for the anabolic response of bone in vivo to PTH treatment has yet to be fully elucidated. Unexpectedly, PTH exerted powerful inhibitory effects on cell growth, differentiation and bone formation. Moreover, mRNA expression of sclerostin, a key endogenous inhibitor of bone formation, was downregulated by PTH treatment. These findings indicate that the in vivo anabolic response to PTH involves additional factors that override its direct inhibitory action on osteoblasts. Collectively, the results presented in this thesis strengthen the notion that the production of collagen by connective tissue cells is dependent on oxygen and the vascular supply, and implicate the vasculature in mediating the effects of anabolic hormones on bone.
|Title:||Function of cells producing type I collagen: potential influence of the vasculature|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Due to copyright reasons, the following article has been removed from the digital copy of this thesis: Orriss, I. R., Knight, G. E., Utting, J. C., Taylor, S. E., Burnstock, G. and Arnett, T. R. (2009), Hypoxia stimulates vesicular ATP release from rat osteoblasts. Journal of Cellular Physiology, 220: 155–162. doi: 10.1002/jcp.21745|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology|
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