Obesity, Biomechanics, and Inflammation in Osteoarthritis

Summary

Principal Investigator: Farshid Guilak
Abstract: DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting an estimated 27 million people in the United States. As the prevalence of obesity has risen dramatically in the past two decades, we now know that obesity is likely to be the primary preventable risk factor for OA. The goal of this project is to examine the influence of dietary fatty acids on obesity-associated OA in mice, and to examine their interaction with altered biomechanical and pro-inflammatory cytokines using various in vivo and in vitro models. We propose that low-grade chronic systemic inflammation - due to obesity or pro- inflammatory fatty acids in the diet - acts in synergy with local inflammatory cytokines or altered mechanical loading following injury to promote a state of inflammation and matrix degradation in the articular cartilage. We will pursue the following aims: In Aim 1, we will examine the role of a high-fat lard- based diet in the development of OA in a leptin-receptor deficient mouse (db/db), and we will also measure osteoarthritic changes in diet-induced obese mice fed high-fat diets high in saturated and monounsaturated fatty acids, or omega-3 or omega-6 poly-unsaturated fatty acids. In Aim 2, we will examine the effects of obesity (via high-fat diet or leptin deficiency) and weight loss on the progression of OA in a destabilized medial meniscus model of mouse OA. In Aim 3, we will use controlled in vitro models of cartilage explant loading to examine the effects of mechanical stress in combination with pro- inflammatory cytokines and fatty acids on the anabolic and catabolic activities of the chondrocytes, as measured by biomarker production, gene expression, and protein synthesis of collagen II and aggrecan. Detailed studies of the interactions between specific biomechanical factors, pro-inflammatory mediators, and tissue metabolism in articular cartilage will improve our understanding of the pathology of the OA, particularly as it relates in vivo to "biomechanical" factors such as obesity, injury, or weight loss. The results of this study will provide new insight into key elements of the pathogenesis of OA, and ultimately could lead to new treatments that exploit physical, dietary, and molecular therapies to prevent disease.
Funding Period: -----------------201 - ----------------2018
more information: NIH RePORT

Top Publications

  1. pmc High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase
    Rebecca E Wilusz
    Department of Orthopaedic Surgery, Duke University Medical Center, USA Department of Biomedical Engineering, Duke University, USA
    J Mech Behav Biomed Mater 38:183-97. 2014
  2. pmc Interaction of lubricin with type II collagen surfaces: adsorption, friction, and normal forces
    Debby P Chang
    Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708, USA Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, NC 27708, USA
    J Biomech 47:659-66. 2014
  3. pmc TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading
    Christopher J O'Conor
    Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710
    Proc Natl Acad Sci U S A 111:1316-21. 2014
  4. pmc Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage
    Jonathan M Brunger
    Departments of Orthopaedic Surgery and Cell Biology, Duke University Medical Center, Durham, NC 27710
    Proc Natl Acad Sci U S A 111:E798-806. 2014
  5. pmc Tissue-engineered cartilage with inducible and tunable immunomodulatory properties
    Katherine A Glass
    Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
    Biomaterials 35:5921-31. 2014
  6. pmc Biomechanics and mechanobiology in functional tissue engineering
    Farshid Guilak
    Departments of Orthopaedic Surgery and Biomedical Engineering, Duke University Medical Center, 375 MSRB, Box 3093, Durham, NC 27710, USA Electronic address
    J Biomech 47:1933-40. 2014

Research Grants

Detail Information

Publications6

  1. pmc High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase
    Rebecca E Wilusz
    Department of Orthopaedic Surgery, Duke University Medical Center, USA Department of Biomedical Engineering, Duke University, USA
    J Mech Behav Biomed Mater 38:183-97. 2014
    ..Our results provide new evidence for high resistance of PCM micromechanical properties to PG digestion and suggest a potential role for elastase in the degradation of the ECM and PCM. ..
  2. pmc Interaction of lubricin with type II collagen surfaces: adsorption, friction, and normal forces
    Debby P Chang
    Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC 27708, USA Center for Biologically Inspired Materials and Material Systems, Duke University, Durham, NC 27708, USA
    J Biomech 47:659-66. 2014
    ....
  3. pmc TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading
    Christopher J O'Conor
    Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710
    Proc Natl Acad Sci U S A 111:1316-21. 2014
    ....
  4. pmc Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage
    Jonathan M Brunger
    Departments of Orthopaedic Surgery and Cell Biology, Duke University Medical Center, Durham, NC 27710
    Proc Natl Acad Sci U S A 111:E798-806. 2014
    ..This method opens new avenues in the development of bioactive implants that circumvent the need for ex vivo tissue generation by enabling the long-term goal of in situ tissue engineering...
  5. pmc Tissue-engineered cartilage with inducible and tunable immunomodulatory properties
    Katherine A Glass
    Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27710, USA Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
    Biomaterials 35:5921-31. 2014
    ..The ability of functional engineered cartilage to deliver tunable anti-inflammatory cytokines to the joint may enhance the long-term success of therapies for cartilage injuries or osteoarthritis. ..
  6. pmc Biomechanics and mechanobiology in functional tissue engineering
    Farshid Guilak
    Departments of Orthopaedic Surgery and Biomedical Engineering, Duke University Medical Center, 375 MSRB, Box 3093, Durham, NC 27710, USA Electronic address
    J Biomech 47:1933-40. 2014
    ..Consideration of these principles in the design process will hopefully improve the safety, efficacy, and overall success of engineered tissue replacements. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..
  3. Genetic dissection of the role of chondroitin sulfate in cartilage
    Yu Yamaguchi; Fiscal Year: 2013
    ..By these studies, we wish to gain novel insight into the molecular mechanisms of cartilage degeneration in OA, and to translate our observations in mice into the identification of novel susceptibility genes for human OA. ..
  4. Engineering Lubrication in Tissue Engineered Cartilage
    AKEPATI HARI REDDI; Fiscal Year: 2013
    ..The successful validation of lubricated, tissue engineered construct functionality the mouse model would lead to larger animal studies and potential clinical translation. ..
  5. Osmotic Signaling in Chondrocyte Aging and Osteoarthritis
    CHRISTOPHER JOSEPH O'CONOR; Fiscal Year: 2013
    ....
  6. The Effect of Age on Functional ACL Healing
    Martha M Murray; Fiscal Year: 2013
    ..Success in this endeavor could improve the care of hundreds of thousands of adolescent and adult patients with ACL tears each year. ..
  7. ER Stress: Role in OA
    Raghunatha R Yammani; Fiscal Year: 2013
    ....
  8. Mechanical and Osmotic Signaling in Chondrocytes
    Farshid Guilak; Fiscal Year: 2013
    ....
  9. Centers of Research Translation (CoRT)
    Kenneth G Saag; Fiscal Year: 2013
    ..abstract_text> ..
  10. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  11. Oxidative Stress and the Development of Osteoarthritis
    Richard F Loeser; Fiscal Year: 2013
    ....
  12. Strength Training and Arthritis Trial
    Stephen P Messier; Fiscal Year: 2013
    ....
  13. Knee Osteoarthritis: Meniscus Kinematics and Articular Cartilage Degeneration
    Toran D MacLeod; Fiscal Year: 2013
    ..The research-training program includes course work in designing and implementing clinical research, a rich research environment, and structured mentoring for the applicant. ..
  14. Ultrashort TE MR Imaging of Femorotibial Cartilage
    Christine B Chung; Fiscal Year: 2013
    ..abstract_text> ..
  15. Rapid Integration of Articular Cartilage Implants Using Photochemical Bonding
    MARC ELLIOT LEVENSTON; Fiscal Year: 2013
    ..The innovation of this work is in the development of a clinically feasibl photochemical bonding approach suitable for treating full thickness cartilage defects and achieving durable lateral integration. ..
  16. VISCOELASTIC PROPERTIES OF NORMAL AND OA CHONDRONS
    Farshid Guilak; Fiscal Year: 2013
    ..A better understanding of these pathways will hopefully lead to the development of new pharmaceutical or biophysical interventions for the treatment of osteoarthritis. ..
  17. Controlling mechanical signal transduction to treat osteoarthritis
    WOLFGANG B LIEDTKE; Fiscal Year: 2013
    ..Beyond single-trauma induced joint injury, we also see as a clear target the more chronic joint injury facilitated by obesity. ..
  18. Tribosupplementation of Injured Joints
    Gregory D Jay; Fiscal Year: 2013
    ..The PI is also a practicing emergency physician and already collaborates with the sub-contract Co-I, who has also performed several large animal studies to date. ..
  19. Cartilage, Bone and Marrow Interactions in Knee OA
    Ravinder Reddy Regatte; Fiscal Year: 2013
    ..The current R01 proposal will develop a more effective means of identifying individuals at higher risk for OA progression via quantitative assessment of whole knee joint via ultra high field (7T) MRI system. ..
  20. Modulation of the Immune System to Improve Ligament/Ligament Graft Healing
    Ray Vanderby; Fiscal Year: 2013
    ..Each one of these would be of great significance and each would have much broader applications than those explored herein. ..
  21. Diagnosis of Osteochondrosis using high field MRI
    CATHY SUE CARLSON; Fiscal Year: 2013
    ..Dr. Carlson's long-term career goal is to remain in academic research, obtain and maintain RO1 funding for this project, and to devote at least 75% of her effort to research activities. ..
  22. The Toll-like receptor pathway in Meniscal Injury and Osteoarthritis
    CARLA ROSE SCANZELLO; Fiscal Year: 2013
    ..As we currently have no interventions for early OA that impact disease progression, defining important pathways in early disease is essential. ..
  23. HMGB2 in cartilage homeostasis, aging and osteoarthritis
    Martin K Lotz; Fiscal Year: 2013
    ..The proposed studies will provide insights into mechanisms of early degenerative changes in the articular cartilage and may permit development of preventive and therapeutic strategies for OA. ..
  24. Pain Mechanisms of Knee Joint Osteoarthritis
    HEE JEONG IM SAMPEN; Fiscal Year: 2013
    ....
  25. Development of an ex vivo derived laser drilled temporomandibular disc scaffold
    PETER STUART MCFETRIDGE; Fiscal Year: 2013
    ..These advances may lead to improved treatment options for patients suffering with irreparably damaged Temporomandibular Joint (TMJ) discs. ..
  26. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..