Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice.

Abstract

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.

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Published Version (Please cite this version)

10.1186/ar3068

Publication Info

Griffin, Timothy M, Beverley Fermor, Janet L Huebner, Virginia B Kraus, Ramona M Rodriguiz, William C Wetsel, Li Cao, Lori A Setton, et al. (2010). Diet-induced obesity differentially regulates behavioral, biomechanical, and molecular risk factors for osteoarthritis in mice. Arthritis Res Ther, 12(4). p. R130. 10.1186/ar3068 Retrieved from https://hdl.handle.net/10161/10876.

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Scholars@Duke

Kraus

Virginia Byers Kraus

Mary Bernheim Distinguished Professor of Medicine

Virginia Byers Kraus, MD, PhD, is the Mary Bernheim Distinguished Professor of Medicine, Professor of Orthopaedic Surgery, Professor of Pathology and a faculty member of the Duke Molecular Physiology Institute in the Duke University School of Medicine. She is a practicing Rheumatologist with over 30 years’ experience in translational musculoskeletal research focusing on osteoarthritis, the most common of all arthritides. She trained at Brown University (ScB 1979), Duke University (MD 1982, PhD 1993) and the Duke University School of Medicine (Residency in Internal Medicine and Fellowship in Rheumatology). Her career has focused on elucidating osteoarthritis pathogenesis and translational research into the discovery and validation of biomarkers for early osteoarthritis detection, prediction of progression, monitoring of disease status, and facilitation of therapeutic developments. She is co-PI of the Foundation for NIH Biomarkers Consortium Osteoarthritis project. Trained as a molecular biologist and a Rheumatologist, she endeavors to study disease from bedside to bench.

Wetsel

William Christopher Wetsel

Associate Professor in Psychiatry and Behavioral Sciences

RESEARCH INTERESTS
Last Updated: 27 October 2020

My laboratory uses genetically-modified mice to study the roles that certain genes and gene products play in the presentation of abnormal neuroendocrine, neurological, and psychiatric responses. Traditionally, the 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 conditions have depended upon phenomenology.  The use of genetic technologies has allowed specific genes in selected cells and in neural pathways to be related to certain molecular, biochemical, cellular, physiological, and behavioral dysfunctions. As the Director of the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University (http://sites.duke.edu/mousebehavioralcore/), we have phenotyped many different lines of inbred and mutant mice for my own work as well as for investigators at Duke and at other research institutions. As a consequence, we have helped to develop many different mouse genetic models of neuroendocrine and neuropsychiatric illness. We are working also with academic medicinal chemists and/or certain pharmacological/biotechnological companies to identify novel compounds that will ameliorate abnormal responses in various mutant mouse models. Some of these preclinical studies have formed a basis for clinical trials in humans.


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