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Open Access Research article

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

Timothy M Griffin16, Beverley Fermor1, Janet L Huebner2, Virginia B Kraus2, Ramona M Rodriguiz3, William C Wetsel34, Li Cao5, Lori A Setton15 and Farshid Guilak15*

Author Affiliations

1 Department of Surgery, Duke University Medical Center, 375 Medical Sciences Research Building, Durham, NC 27710, USA

2 Department of Medicine, Duke University Medical Center, 2100 Erwin Road, Durham, NC 27710, USA

3 Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, 2100 Erwin Road, Durham, NC 27710, USA

4 Departments of Neurobiology and Cell Biology, Duke University Medical Center, 2100 Erwin Road, Durham, NC 27710, USA

5 Department of Biomedical Engineering, Duke University, 136 Hudson Hall, Durham, NC 27708, USA

6 Current address: Program in Free Radical Biology and Aging, Oklahoma Medical Research Foundation, Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, 825 NE 13th St, Oklahoma City, OK 73104 USA

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Arthritis Research & Therapy 2010, 12:R130  doi:10.1186/ar3068


See related editorial by van der Kraan, http://arthritis-research.com/content/12/4/130

Published: 6 July 2010

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.