Oxidative Stress and the Development of Osteoarthritis

Summary

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

Top Publications

  1. pmc Aging processes and the development of osteoarthritis
    Richard 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
  2. pmc Osteoarthritis year in review 2013: biology
    R 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
  3. pmc Brief report: stress-inducible nuclear protein 1 regulates matrix metalloproteinase 13 expression in human articular chondrocytes
    Raghunatha R Yammani
    Wake Forest School of Medicine, Winston Salem, North Carolina
    Arthritis Rheumatol 66:1266-71. 2014
  4. pmc Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1
    Richard 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

Research Grants

  1. Role of redox state in ovarian cancer response to cisplatin
    Larry W Daniel; Fiscal Year: 2013
  2. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
  3. Integrin Function in Cartilage
    Richard F Loeser; Fiscal Year: 2013
  4. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
  5. Centers of Research Translation (CoRT)
    Kenneth G Saag; Fiscal Year: 2013
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  7. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
  8. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
  9. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  10. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc Aging processes and the development of osteoarthritis
    Richard 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...
  2. pmc Osteoarthritis year in review 2013: biology
    R 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. ..
  3. pmc Brief report: stress-inducible nuclear protein 1 regulates matrix metalloproteinase 13 expression in human articular chondrocytes
    Raghunatha 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...
  4. pmc Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1
    Richard 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)...

Research Grants30

  1. Role of redox state in ovarian cancer response to cisplatin
    Larry W Daniel; Fiscal Year: 2013
    ..We will use our newly developed reagents that react specifically with oxidized proteins and act as a tag to allow identification of the protein targets for oxidation. ..
  2. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  3. Integrin Function in Cartilage
    Richard F Loeser; Fiscal Year: 2013
    ..This represents a significant advance over the general inhibition of ROS production which has not proven successful in treating conditions promoted by excessive ROS, including arthritis. ..
  4. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
    ..abstract_text> ..
  5. Centers of Research Translation (CoRT)
    Kenneth G Saag; Fiscal Year: 2013
    ..abstract_text> ..
  6. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  7. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  8. COBRE for Skeletal Health and Repair
    Qian Chen; Fiscal Year: 2013
    ..This multidisciplinary approach is absolutely necessary to develop translational strategies for prevention and treatment of skeletal joint diseases. ..
  9. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  10. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  11. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  12. The role of mitochondrial protein thiol modification in endothelial dysfunction
    AIMEE LEIGH LANDAR; Fiscal Year: 2013
    ..This project tests the hypothesis that mitochondrial protein thiols are damaged in atherosclerosis and contribute to vascular dysfunction. ..
  13. Mapping local strains in cartilage during injurious impact loading
    ITAI COHEN; Fiscal Year: 2013
    ....
  14. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  15. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  16. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  17. MItochondrial Dysfunction in Cardiac Hypertrophy and Failure
    Jennifer E Van Eyk; Fiscal Year: 2013
    ..A vicious circle of these complex deleterious interactions could thus mediate decompensation of the failing heart. (End of Abstract) ..
  18. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  19. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  20. Core Center for Musculoskeletal Disorders
    Louis J Soslowsky; Fiscal Year: 2013
    ..abstract_text> ..