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

Kimberly Waller,Ling Zhang,Gregory Jay

doi:10.3390/ijms18061252

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.

Highlights

Deficiency of lubricin (PRG4), the principal boundary lubricant in cartilage, contributes to progressive joint failure that is hallmarked by increased joint friction, superficial and upper intermediate zone apoptosis, and synovial hyperplasia, as shown in Prg4-null mice [1] and patients with camptodactyl-arthropathy-coxa vara-pericarditis (CACP) syndrome [2,3]
Cartilage compression alerts mitochondria within chondrocytes via the cytoskeleton [18] and mitochondrial dysfunction has been linked to osteoarthritis [19]
Deficiency of PRG4 at the articular surface results in dyscrasia of mitochondria within chondrocytes characterized by activation of intrinsic apoptosis pathways resulting in caspase-3 activation

Summary

Introduction

Deficiency of lubricin (PRG4), the principal boundary lubricant in cartilage, contributes to progressive joint failure that is hallmarked by increased joint friction, superficial and upper intermediate zone apoptosis, and synovial hyperplasia, as shown in Prg4-null mice [1] and patients with camptodactyl-arthropathy-coxa vara-pericarditis (CACP) syndrome [2,3]. Patients with CACP have used non-steroidal anti-inflammatory medications to seek symptom relief, which suggests that inflammation may play a role in the lubricin-null joint pathology that hitherto was thought to be a non-inflammatory arthropathy. Cartilage surfaces of Prg4 ́/ ́ mice are biofouled with albumin eIpnti.sJo. Mdiocl. Cartilage surfaces of Prg4−/− mice oafr1e7 biofouled with albumin and other synovial fluid non-lubricating constituents [4]. In the absence of lubricin, Prg4−/− joints may experience inflammation due to elevated friction. TthheesperestsuendcieesoafrteherenleevoaenptittooppeactaieunsetsdwbyiththCeAniCtrPossyylnadtiroonmoef Canyds1o6t3hienrscawsiptahster-a3n, swiehnicthloisssinohf iPbRitGor4y. iTnhiensfelasmtumdaietsorayrejorienletvdainset atosepsastuiecnhtsaswtirtahuCmAaCtiPc isnyjnudrireosmwehainchd aortheekrnsowwitnhttorapnlsaiceentalposastioenf tPRatGr4isikn fionrfloasmtemoaarttohrryitjiosi(nOt Adi)s.eases such as traumatic injuries which are known to place a patient at risk for osteoarthritis (OA)

Methods

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Discussion

Conclusion