The overall goal of this proposal is to determine whether the development of osteoarthritis (OA) following traumatic joint injury is due to the damage of mitochondria via opening of the Mitochondrial Permeability Transition Pore (MPTP) in articular chondrocytes and whether protecting mitochondria via inhibition of MPTP opening will effectively prevent or delay post-traumatic OA. OA is a debilitating degenerative joint disease characterized by an irreversible loss of articular cartilage. Such changes result in disabling joint pain that is treated only through palliative therapy, as there is currently no treatment to prevent OA progression or induce cartilage regeneration. Therefore, the search for new approaches in the treatment of OA is of utmost importance. Our proposal is expected to pave the way for such new approaches targeted at protecting and improving mitochondrial function in the cartilage. Deterioration of mitochondrial function due primarily to MPTP opening is known to contribute to degenerative processes in various organs, such as the brain and the heart. Very little is known, however, about the role of mitochondria and the MPTP in cartilage physiology and pathology. Knowing that oxidative stress is present in OA and that mitochondria are both major sources and major sensors of oxidative stress, we hypothesize that mitochondrial dysfunction via MPTP opening contributes to OA pathogenesis. To test this, we will use this high risk/high impact R21 funding mechanism to compare OA development in mouse knees after induced meniscal/ligamentous injury in wild type (WT) animals and in genetically modified mice where mitochondrial function in articular chondrocytes is protected from MPTP opening (chondrocyte-specific Cyclophilin D conditional knockout (CypD cKO) mice, AcanCreERT2/+; CypDfl/fl). We will also explore the pathogenic signaling mechanisms that connect MPTP opening in chondrocytes to joint tissue demise. We will test if MPTP-mediated disruption of mitochondrial membranes and ensuing mtDNA release into the cytosol trigger inflammatory signaling via TLR- and NF?B-dependent mechanisms. We expect that protecting mitochondrial function via MPTP inhibition will protect chondrocytes, their surrounding cartilage matrix, synovial tissues, and subchondral bone from injury-induced OA. If successful, this project will enhance our understanding of the role of mitochondria in the pathogenesis of OA and provide valuable clues and preliminary data for future R01-level grant submissions.
The proposed research is relevant to public health because it has a potential to lead to development of new strategies to prevent and/or treat osteoarthritis. It is also expected to advance the field of cartilage biology by elucidating yet unknown mechanisms connecting oxidative damage in chondrocyte mitochondria and cartilage degeneration. This is highly relevant to the NIH mission of developing fundamental knowledge that will help to reduce the burdens of human disability.
