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

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 (O-₂) 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.

• Authors: Kimberly A Waller, Ling X Zhang, Gregory D Jay
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 18 Issue 6 (Jun 11 2017) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 28604608 (Publication Type: Journal Article)

Chemical References

• PRG4 protein, human
• Prg4 protein, mouse
• Proteoglycans
• Casp3 protein, mouse
• Casp9 protein, mouse
• Caspase 3
• Caspase 9

Topics

• Animals
• Apoptosis
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Chondrocytes (drug effects, metabolism, pathology)
• Disease Models, Animal
• Friction
• Injections, Intra-Articular
• Joint Diseases (metabolism, pathology)
• Joints (drug effects, metabolism, pathology)
• Mice
• Mice, Knockout
• Mitochondria (drug effects, metabolism, pathology)
• Proteoglycans (administration & dosage, genetics, pharmacology)
• Signal Transduction