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Am J Physiol Cell Physiol 281: C833-C839, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 3, C833-C839, September 2001

Phosphate-induced chondrocyte apoptosis is linked to nitric oxide generation

Cristina C. Teixeira1, Kyle Mansfield1, Caryn Hertkorn2, Harry Ischiropoulos2, and Irving M. Shapiro1

1 Department of Biochemistry, School of Dental Medicine, Philadelphia, and 2 Stokes Research Institute, Children's Hospital at Philadelphia and Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

An elevation in inorganic phosphate (Pi) concentration activates epiphyseal chondrocyte apoptosis. To determine the mechanism of apoptosis, tibial chondrocytes were treated with Pi, and nitrate/nitrite (NO<UP><SUB>3</SUB><SUP>−</SUP></UP>/NO<UP><SUB>2</SUB><SUP>−</SUP></UP>) levels were determined. Pi induced a threefold increase in the NO<UP><SUB>3</SUB><SUP>−</SUP></UP>/NO<UP><SUB>2</SUB><SUP>−</SUP></UP> concentration; inhibitors of nitric oxide (NO) synthase activity and Pi transport significantly reduced NO<UP><SUB>3</SUB><SUP>−</SUP></UP>/NO<UP><SUB>2</SUB><SUP>−</SUP></UP> levels and prevented cell death. Furthermore, a dose-dependent increase in cell death was observed after exposure of chondrocytes to S-nitrosoglutathione. Pi increased caspase 3 activity 2.7-fold. Both caspase 1 and caspase 3 inhibitors protected chondrocytes from Pi-induced apoptosis. Pi caused a significant decrease in the mitochondrial membrane potential, while NO synthase inhibitors maintained mitochondrial function. While Pi caused thiol depletion, inhibition of Pi uptake or NO generation served to maintain glutathione levels. The results suggest that NO serves to mediate key metabolic events linked to Pi-dependent chondrocyte apoptosis.

epiphyseal chondrocyte; nitric oxide synthase; caspase


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C. S. Adams and I. M. Shapiro
THE FATE OF THE TERMINALLY DIFFERENTIATED CHONDROCYTE: EVIDENCE FOR MICROENVIRONMENTAL REGULATION OF CHONDROCYTE APOPTOSIS
Critical Reviews in Oral Biology & Medicine, November 1, 2002; 13(6): 465 - 473.
[Abstract] [Full Text] [PDF]


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