Oxidative Stress and the Development of Osteoarthritis
Principal Investigator: Richard F Loeser
Abstract: DESCRIPTION (provided by applicant): The long-term objective of this project is to determine the mechanisms by which oxidative stress contributes to the pathogenesis of osteoarthritis (OA) by focusing on mechanisms by which reactive oxygen species (ROS) alter cell signaling in the articular cartilage and meniscus. Oxidative stress results when levels of ROS exceed the anti-oxidant capacity of cells. Studies to date suggest that oxidative stress can contribute to fundamental processes found in OA, including excessive catabolic relative to anabolic activity and cell death, but the mechanisms responsible have not been defined. Mitochondria are an important source of intracellular ROS and our preliminary studies demonstrate that overexpression of the anti-oxidant enzyme catalase, targeted to the mitochondria in transgenic mice, reduces the severity of age-associated OA. We propose that in OA, pathological levels of ROS are generated by the mitochondria which, when combined with a deficient anti-oxidant capacity, results in excessive protein oxidation that shifts cell signaling to favor catabolic over anabolic signaling and to promote cell death. Our studies will focus on mechanisms by which excessive levels of ROS disrupt the IRS-1-PI-3 kinase-Akt signaling pathway. Akt plays a central role in integrating anabolic and catabolic signaling as well as in promoting cell survival. We have found that in OA chondrocytes and in normal cells induced to exhibit oxidative stress, Akt activation is inhibited and this is associated with reduced matrix synthesis and increased susceptibility to cell death. We will pursue the following specific aims: 1) Determine the mechanism for inhibition of IRS-1-PI-3kinase-Akt signaling in chondrocytes during oxidative stress and test the hypothesis that excessive levels of ROS oxidize specific proteins that activate the MAP kinase pathway which inhibits Akt1 activation through inhibition of IRS-1-PI-3 kinase signaling and 2) Determine the effects of overexpression of catalase targeted to the mitochondria on the development of osteoarthritis in mice and test the hypothesis that overexpression of catalase will reduce OA severity. Effects on the signaling proteins discovered to be important in inhibiting Akt will be studied. The discoveries made by this work will be used to develop new therapies that would replace the untargeted general anti-oxidant approach with more a more targeted approach aimed at the specific pathways affected by oxidative stress and contributing to OA.
Funding Period: 2012-09-30 - 2017-05-31
more information: NIH RePORT
- Aging processes and the development of osteoarthritisRichard F Loeser
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA
Curr Opin Rheumatol 25:108-13. 2013..The most recent literature in this area was reviewed in order to update investigators on the status of the field...
- Osteoarthritis year in review 2013: biologyR F Loeser
Department of Internal Medicine, Section of Molecular Medicine and The Wake Forest Arthritis and Musculoskeletal Diseases Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA Electronic address
Osteoarthritis Cartilage 21:1436-42. 2013..Key findings in these areas were summarized and implications for future therapies were discussed. ..
- Brief report: stress-inducible nuclear protein 1 regulates matrix metalloproteinase 13 expression in human articular chondrocytesRaghunatha R Yammani
Wake Forest School of Medicine, Winston Salem, North Carolina
Arthritis Rheumatol 66:1266-71. 2014..The present study was undertaken to determine whether chondrocytes express Nupr1 and whether Nupr1 regulates matrix metalloproteinase 13 (MMP-13) expression...
- Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1Richard F Loeser
University of North Carolina, Chapel Hill, and Wake Forest University School of Medicine, Winston Salem, North Carolina
Arthritis Rheumatol 66:2201-9. 2014..To determine the effects of aging and oxidative stress on the response of human articular chondrocytes to insulin-like growth factor 1 (IGF-1) and osteogenic protein 1 (OP-1)...
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