Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice.
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INTRODUCTION: Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet. METHODS: Female C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis. RESULTS: High susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants. CONCLUSIONS: These results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.
Mice, Inbred C57BL
Severity of Illness Index
Temporomandibular Joint Disorders
Tissue Culture Techniques
Published Version (Please cite this version)10.1186/ar3068
Publication InfoCao, L; Fermor, B; Griffin, TM; Guilak, Farshid; Huebner, JL; Kraus, Virginia Byers; ... Wetsel, William Christopher (2010). Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice. Arthritis Res Ther, 12(4). pp. R130. 10.1186/ar3068. Retrieved from https://hdl.handle.net/10161/10876.
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Lazlo Ormandy Professor of Orthopaedic Surgery
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Professor of Medicine
My special area of expertise is as a clinician scientist investigating osteoarthritis. Osteoarthritis is the most common form of joint disease in man and its incidence increases with age. It is a problem of increasing concern to the medical community due to the increasing longevity of the population. Trained as a molecular biologist and a Rheumatologist, I endeavor to study this disease from bedside to bench. The work in this laboratory focuses on osteoarthritis and deals w
Adjunct Professor of Biomedical Engineering
Research in Setton's laboratory is focused on the role of mechanical factors in the degeneration and repair of soft tissues of the musculoskeletal system, including the intervertebral disc, articular cartilage and meniscus. Work in the Laboratory is focused on engineering and evaluating materials for tissue regeneration and drug delivery. Studies combining engineering and biology are also used to determine the role of mechanical factors to promote and control healing of cartilaginous tissues. Re
Associate Professor in Psychiatry and Behavioral Sciences
RESEARCH INTERESTS Last Updated: 31 December 1997 My laboratory uses genetically-modified mice to study the roles that certain genes and gene products play in the expression of abnormal neuroendocrine, neurological, and psychiatric responses. Traditionally, an identification of neuroendocrine dysfunction has involved biochemical analyses of hormonal responses, those for neurological disorders have relied upon behavioral and postmortem analyses, and those for psychiatric co
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