Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs.
OBJECTIVE
Because articular chondrocytes reside in a hypoxic milieu, anaerobic glycolysis is central in generating ATP to support chondrocyte matrix synthesis and viability, with mitochondrial oxidative phosphorylation possibly providing physiologic reserve ATP generation. Nitric oxide (NO) potently suppresses mitochondrial oxidative phosphorylation. Because enhanced cartilage NO generation occurs in osteoarthritis (OA), we systematically tested for mitochondrial dysfunction in the pathogenesis of OA.


METHODS
We assessed chondrocytes for ATP depletion and for in situ changes in mitochondrial ultrastructure prior to and during the evolution of spontaneous knee OA in male Hartley guinea pigs, a model in which chondrocalcinosis also supervenes.


RESULTS
Spontaneous NO release from knee cartilage samples in organ culture doubled between ages 2 months and 8 months as knee OA developed. Concomitantly, chondrocyte intracellular ATP levels declined by approximately 50%, despite a lack of mitochondrial ultrastructure abnormalities in knee chondrocytes. As ATP depletion progressed with aging in knee chondrocytes, an increased ratio of lactate to pyruvate was observed, consistent with an adaptive augmentation of glycolysis to mitochondrial dysfunction. Furthermore, we observed progressive elevation of chondrocyte ATP-scavenging nucleotide pyrophosphatase/phosphodiesterase (NPP) activity and extracellular levels of the NPP enzymatic end product inorganic pyrophosphate (PPi), which stimulate chondrocalcinosis.


CONCLUSIONS
Profound chondrocyte ATP depletion develops in association with heightened NO generation in guinea pig knee OA. Increased NPP activity and concordant increases in extracellular PPi, which are strongly associated with human aging-associated degenerative arthropathy and directly stimulate chondrocalcinosis, may be primarily driven by chondrocyte ATP depletion. Our findings implicate a decreased mitochondrial bioenergetic reserve as a pathogenic factor in both degenerative arthropathy and chondrocalcinosis in aging.
Johnson
Kristen
K
Veterans Affairs Medical Center, and University of California, San Diego, 92161, USA.
Svensson
Camilla I
CI
Etten
Deborah Van
DV
Ghosh
Soumitra S
SS
Murphy
Anne N
AN
Powell
Henry C
HC
Terkeltaub
Robert
R
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000378:metabolism*; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011755:Pyrophosphatases / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
D006025:Glycosaminoglycans; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D011503:Transglutaminases; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C405782:nucleotide pyrophosphatase - phosphodiesterase I