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.
Osteoarthritis is the most common cause of chronic disability in older adults but treatments to slow the progression of the disease are lacking. The results from this project will provide new information about basic mechanisms relevant to joint tissue breakdown in osteoarthritis. This information is needed in order to discover new targets for slowing or stopping the progression of the disease.
|Loeser, Richard F; Collins, John A; Diekman, Brian O (2016) Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12:412-20|
|Collins, John A; Wood, Scott T; Nelson, Kimberly J et al. (2016) Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes. J Biol Chem 291:6641-54|
|Wood, Scott T; Long, David L; Reisz, Julie A et al. (2016) Cysteine-Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments. Arthritis Rheumatol 68:117-26|
|Greene, M A; Loeser, R F (2015) Function of the chondrocyte PI-3 kinase-Akt signaling pathway is stimulus dependent. Osteoarthritis Cartilage 23:949-56|
|Greene, M A; Loeser, R F (2015) Aging-related inflammation in osteoarthritis. Osteoarthritis Cartilage 23:1966-71|
|Long, D L; Ulici, V; Chubinskaya, S et al. (2015) Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is increased in osteoarthritis and regulates chondrocyte catabolic and anabolic activities. Osteoarthritis Cartilage 23:1523-31|
|Stone, A V; Vanderman, K S; Willey, J S et al. (2015) Osteoarthritic changes in vervet monkey knees correlate with meniscus degradation and increased matrix metalloproteinase and cytokine secretion. Osteoarthritis Cartilage 23:1780-9|
|Loeser, Richard F; Gandhi, Uma; Long, David L et al. (2014) Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1. Arthritis Rheumatol 66:2201-9|
|Yammani, Raghunatha R; Loeser, Richard F (2014) Brief report: stress-inducible nuclear protein 1 regulates matrix metalloproteinase 13 expression in human articular chondrocytes. Arthritis Rheumatol 66:1266-71|
|Loeser, Richard F (2013) Aging processes and the development of osteoarthritis. Curr Opin Rheumatol 25:108-13|
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