Therapeutic Targeting of Mitochrondria to Prevent Osteoarthritis
Principal Investigator: Lisa Fortier
DESCRIPTION (provided by applicant):
Osteoarthritis (OA) is the leading cause of chronic disability in the United States. Post-traumatic osteoarthritis (PTOA) develops secondary to joint trauma with clinical disease (pain and dysfunction) often lagging months to years behind the initiating injury. No therapies exist to prevent or slow progression of PTOA. Mitochondrial (MT) dysfunction mediates the pathogenesis of many complex and seemingly unrelated diseases, from diabetes to Alzheimer’s and can occur secondary to mechanical injury in syndromes such as intraocular pressure-induced retinopathy in glaucoma. MT abnormalities exist in chondrocytes from late-stage OA patients, however the role of MT dysfunction in the initiation and early pathogenesis of PTOA has not been investigated. Our preliminary data show that mechanical injury to cartilage induces MT dysfunction, MT membrane depolarization, and cell death within 2 hours of injury, as well as MT-mediated apoptosis within 24 hours. Our hypothesis is that targeted mitoprotective therapy will attenuate the development of PTOA. This study represents the first testing of SS peptides, a new mitoprotective class of drugs, in cartilage. SS peptides are water soluble, cell-permeable, and concentrate over 1000 fold in the inner MT membrane (IMM). They prevent MT dysfunction, stabilize the IMM, improve MT bioenergetics, reduce reactive oxygen species generation, and prevent apoptotic cell death. Our preliminary data show that in cartilage, SS-31 prevents MT depolarization and dramatically reduces cell death after impact injury. SS peptides are in Phase II clinical trials for other MT-mediated diseases, which could result in accelerated implementation of SS peptides into clinical practice for PTOA. Current OA therapies are limited to symptomatic relief. Establishing MT as a novel therapeutic target after joint injury could result in the first approach to alter the disease course and prevent irreversible joint dysfunction and chronic pain.