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Int. J. Mol. Sci. 2017, 18(6), 1252; doi:10.3390/ijms18061252

Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice

1
Department of Orthopedics, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA
2
Department of Emergency Medicine, Warren Alpert School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA
3
School of Engineering, Brown University, Providence, RI 02912, USA
4
Department of Emergency Medicine, Rhode Island Hospital, Coro West, 1 Hoppin Street, Suite 106, Providence, RI 02903, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Charles J. Malemud and Ali Mobasheri
Received: 14 April 2017 / Revised: 20 May 2017 / Accepted: 27 May 2017 / Published: 11 June 2017
(This article belongs to the Special Issue Apoptotic Chondrocytes and Osteoarthritis)
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Abstract

Deficiency of PRG4 (lubricin), the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4−/−) mice. Caspase-3 activity appears to be reversible upon the restitution of Prg4 either endogenously in vivo, in a gene trap mouse, or as an applied lubricant in vitro. In this study we show that intra-articular injection of human PRG4 in vivo in Prg4−/− mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo using a joint pendulum method. Non-lubricated Prg4−/− mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation, and significantly higher levels of peroxynitrite (ONOO and OH) and superoxide (O2) compared to Prg4+/+ and Prg4+/− cartilage. Enzymatic activity levels of caspase 8 across Prg4 mutant mice were not significantly different, indicating no extrinsic apoptosis pathway activation. Western blots showed caspase-3 and 9 activation in Prg4−/− tissue extracts, and the appearance of nitrosylated Cys163 in the active cleft of caspase-3 which inhibits its enzymatic activity. These findings are relevant to patients at risk for arthrosis, from camptodactyl-arthropathy-coxa vara-pericarditis (CACP) syndrome and transient lubricin insufficiency due to trauma and inflammation. View Full-Text
Keywords: caspase-3; apoptosis; friction; lubricin; PRG4; chondrocytes caspase-3; apoptosis; friction; lubricin; PRG4; chondrocytes
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Waller, K.A.; Zhang, L.X.; Jay, G.D. Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice. Int. J. Mol. Sci. 2017, 18, 1252.

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