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Extracellular pH: a fundamental regulator of bone cell function.

Brandao-Burch, A.; (2005) Extracellular pH: a fundamental regulator of bone cell function. Doctoral thesis , University of London. Green open access

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Systemic acidosis is associated with bone loss and impaired bone mineralisation. The aim of this PhD project was to further investigate the action of extracellular pH on the function of osteoclasts and osteoblasts. I showed that blood-derived human osteoclasts exhibited a highly reproducible acid-activation response, with maximal activation close to pH 7.0, and little activity at blood pH (7.4). These experiments also provided strong evidence that accessory cells, such as osteoblasts or stromal cells, are not required for acid-activation of resorption. The pH-activation profile of human osteoclasts was similar to that of the recently discovered KT-sensing human G- protein-coupled receptor OGR1. Expression of OGR1 and TDAG8 (another GPCR) was detected in human osteoclasts and was upregulated by low pH. I obtained evidence that the multifunctional receptor TRPV1, which senses protons, heat and capsaicin, was expressed by human osteoclasts and was also upregulated at pH 7.0. Moreover, I showed that the alkaloid capsaicin strongly stimulated osteoclasts in non- acidified conditions. To date, only pertussis toxin has been reported to activate osteoclasts without co-stimulation by H. Using mouse bone organ cultures I found that resorption-associated factors TRACP, cathepsin K and TRAF-6 were also upregulated by acidosis. The effect of PTH on human osteoclasts was also studied. I showed that PTH directly stimulates human osteoclasts in the absence of osteoblasts, but only when acid-activated. This finding suggests that the dogma that PTH stimulation of osteoclast is osteoblast-mediated may not be correct. Studies using primary rat osteoblast cultures showed that the formation of mineralised bone nodules is inhibited by acidosis. The same pH reduction, which increases Ca2+ and PO43" solubility of hydroxyapatite by 2- and 4-fold respectively, did not alter collagen production or osteoblast proliferation but decreased alkaline phosphatase activity and expression. Thus, the primary effect of acidosis on osteoblast function is to cause a selective inhibition of bone mineralisation. In conclusion, this study showed that the important "double negative" action of acidosis on bone cells is consistent with a pathophysiological role of bone as a reserve of base to buffer excess protons when the kidneys and lungs are unable to maintain acid-base balance within narrow physiological limits.

Type: Thesis (Doctoral)
Title: Extracellular pH: a fundamental regulator of bone cell function.
Identifier: PQ ETD:591800
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/1444494
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