Wellcome PhD Students: Final Year Talks
Thursday 25 September
Room 249, 2nd Floor, Medical Sciences Building, Gower Street
12.30pm: Scott Curran
12.55pm: Kristina Tubby
1.20pm: Miguel Tillo
1.45pm: Alex Sinclair-Wilson
2.10pm: Elena Scarpa
Professor Tim Arnett
Tim Arnett is Professor of Mineralised Tissue Biology. He is a member of the editorial boards of Endocrinology and Calcified Tissue International and a past member of the board of the Journal of Bone & Mineral Research. He is also a member of the Research sub-Committee of the Arthritis Research Campaign. Previously he has served as secretary of the Bone Research Society. His photomicrographs are widely used by academia, industry and the media. He runs a third year BSc course unit in the Biology of the Skeleton at UCL and is closely involved in the teaching of histology to medical students.
I am interested in 'fundamental' regulators of the function of osteoclasts (bone destroying cells) and osteoblasts (bone forming cells). Our work falls into 3 main areas.
Acidosis We discovered that a small pH reduction (acidosis) is necessary to activate osteoclasts to excavate resorption pits on bone surfaces. Simultaneously, acidosis prevents mineralisation of newly-formed bone by osteoblasts. The responses of bone cells to extracellular pH changes probably represent a primitive ‘failsafe’ to correct systemic acidosis by releasing alkaline bone mineral. Acidosis due to disease or diet (and perhaps even excessive exercise) could play a role in bone loss disorders. Current research is focused on understanding the mechanisms by which bone cells recognise and respond to pH changes in their environment.
Hypoxia We found that hypoxia (low oxygen) is a major stimulator of the formation of osteoclasts from mononuclear precursor cells present in blood and bone marrow. Osteoclast formation – and thus bone destruction – is strongly increased when oxygen is reduced to as little as 1% of the atmospheric level. In contrast, we observed that hypoxia blocks the growth and bone-forming capacity of osteoblasts. These observations may help to explain why bone is rapidly lost when the blood supply is reduced or disrupted – eg, as a result of inflammation, infection, tumours, fractures, diabetes, airway diseases and ageing. Significantly, hypoxia also causes tissue acidosis (see above). Our results emphasise the critical role of the vasculature in the maintenance of bone health.
Nucleotides ATP and other nucleotides, acting through P2 receptors, play important and complex regulatory roles as messenger molecules for cell-to-cell communication. We found that numerous P2 receptors are expressed by bone cells and that low concentrations of ATP stimulate both the formation and activity of osteoclasts, whilst selectively blocking mineralisation of newly formed bone by osteoblasts. Recent results show that skeletal changes can occur when P2 receptors are defective or deficient. This works suggests that the ATP – P2 cell signalling system offers potential for novel bone therapeutics.
support Arthritis Research Campaign, BBSRC,
Amgen Ltd, BioLauncher Ltd, European Union
BSc, University of East Anglia
1978 Research Officer, Royal Postgraduate Medical School
1984 PhD, University of London
1984 Postdoctoral Fellow, Columbia University / NY State Dept of Health
1986 Lecturer, UCL
1990 Senior Scientist, OsteoSA / Assistant Professor, University of Texas, San Antonio (sabbatical year)
1997 Senior Lecturer, UCL
2001 Reader, UCL
2007 Professor, UCL
Muzylak M, Arnett TR, Horton MA, Price J (2007) The in vitro effect of pH on osteoclasts and bone resorption in the cat: implications for the pathogenesis of FORL. Journal of Cellular Physiology 213: 144-150.
Orriss IR, Utting JC, Brandao-Burch A, Colston KW, Grubb BR, Burnstock G, Arnett TR (2007) Extracellular nucleotides block bone mineralisation in vitro: evidence for dual inhibitory mechanisms involving both P2Y2 receptors and pyrophosphate. Endocrinology 148: 4208-4216.
Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG (2006) Wnt signalling in osteoblasts regulates expression of receptor activator of NF?B ligand (RANKL) and inhibits osteoclastogenesis in vitro. Journal of Cell Science 119: 1283-1296.
Orriss IR, Knight GE, Ranasinghe S, Burnstock G, Arnett TR (2006) Osteoblast responses to nucleotides increase during differentiation. Bone 39: 300-309.
Utting JC, Robins SP, Brandao-Burch A, Orriss IR, Behar J, Arnett TR (2006) Hypoxia inhibits the growth, differentiation and bone forming capacity of rat osteoblasts. Experimental Cell Research 312: 1693-1702.
Dempster DW, Hughes-Begos CF, Plavetic-Chee K, Brandao-Burch A, Cosman F, Nieves J, Neubort S, Lu SS, Iida-Klein A, Arnett TR, Lindsay R (2005) Normal human osteoclasts formed from peripheral blood monocytes express PTH type 1 receptors and are stimulated by PTH in the absence of osteoblasts. Journal of Cellular Biochemistry 95: 139-148.
Brandao-Burch A, Utting JC, Orriss IR, Arnett TR (2005) Acidosis inhibits bone formation by osteoblasts in vitro by preventing mineralisation. Calcified Tissue International 77: 167-174.
Arnett TR, Gibbons DC, Utting JC, Orriss IR, Hoebertz A, Rosendaal M, Meghji S (2003) Hypoxia is a major stimulator of osteoclast formation and bone resorption. Journal of Cellular Physiology 196: 2-8.
Hoebertz A, Mahendran S, Burnstock G, Arnett TR (2002) ATP and UTP at low concentrations strongly inhibit bone formation by osteoblasts: a novel role for the P2Y2 receptor in bone remodeling. Journal of Cellular Biochemistry 86: 413-419.
Meghji S, Henderson B, Morrison MS, Arnett TR (2001) pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis. American Journal of Physiology 280: E112-119.
Hoebertz A, Meghji S, Burnstock G, Arnett TR (2001) Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y1 receptor on bone cells. FASEB Journal 15: 1139-1148.
Senaratne SG, Primakov G, Mansi JL, Arnett TR, Colston KW (2000) Bisphosphonates induce apoptosis in human breast cancer cell lines. British Journal of Cancer 82: 1459-1468.
Hoebertz A, Townsend-Nicholson A, Burnstock G, Arnett TR (2000) Expression of P2 receptors in bone and cultured bone cells. Bone 27: 503-510.
Morrison M, Turin L, King BF, Burnstock G, Arnett TR (1998) ATP is a potent stimulator of the activation and formation of rodent osteoclasts. Journal of Physiology 511: 495-500.
Arnett TR, Spowage M (1996) Modulation of the resorptive activity of rat osteoclasts by small changes in extracellular pH near the physiological range. Bone 18: 277 279.
Arnett TR, Lindsay R, Kilb JM, Moonga BS, Spowage M, Dempster DW (1996) Selective toxic effects of tamoxifen on osteoclasts: comparison with the effects of oestrogen. Journal of Endocrinology 149: 503 508.
Lees B, Molleson T, Arnett TR, Stevenson JC (1993) Differences in proximal femur density over two centuries. Lancet 341: 673 675.
Gray C, Hukkanen M, Konttinen YT, Terenghi G, Arnett TR, Jones SJ, Burnstock G, Polak JM (1992) Rapid neural growth: calcitonin gene related peptide and substance P containing nerves attain exceptional growth rates in regenerating deer antler. Neuroscience 50: 953 963.
Horton MA, Taylor ML, Arnett TR, Helfrich MH (1991) Arg Gly Asp (RGD) peptides and the anti vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. Experimental Cell Research 195: 368 375.
Arnett TR, Dempster DW (1987) A comparative study of disaggregated chick and rat osteoclasts in vitro: effect of calcitonin and prostaglandins. Endocrinology 120: 602 608.
Arnett TR, Dempster DW (1986) Effect of pH on bone resorption by rat osteoclasts in vitro. Endocrinology 119: 119 124.
Arnett TR (2008) Extracellular pH regulates bone cell function. Journal of Nutrition 138: 415S-418S.
Hoebertz A, Arnett TR, Burnstock G (2003) Regulation of bone resorption and formation by purines and pyrimidines. Trends in Pharmacological Sciences 24: 290-297.
Regulation of bone cell function by acid-base balance. Proceedings
of the Nutrition Society 62: 511-520.
Arnett TR, Burnstock G (Editors) (2006) Nucleotides and Regulation of Bone Cell Function. Taylor and Francis / CRC Press, Boca Raton.
Arnett TR, Henderson B (Editors) (1998) Methods in Bone Biology. Chapman and Hall, London.
Arnett TR (2007) Acid–base regulation of bone metabolism. International Congress Series 1297: 255-267.
Hoebertz A, Arnett TR (2003) Isolated osteoclast cultures. Methods in Molecular Medicine 80: 53-64.
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