Metabolic stress–induced inflammation plays a major role in the development of osteoarthritis in mice
Article first published online: 27 MAR 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 4, pages 1172–1181, April 2012
How to Cite
Gierman, L. M., van der Ham, F., Koudijs, A., Wielinga, P. Y., Kleemann, R., Kooistra, T., Stoop, R., Kloppenburg, M., van Osch, G. J. V. M., Stojanovic-Susulic, V., Huizinga, T. W. and Zuurmond, A.-M. (2012), Metabolic stress–induced inflammation plays a major role in the development of osteoarthritis in mice. Arthritis & Rheumatism, 64: 1172–1181. doi: 10.1002/art.33443
- Issue published online: 2 MAR 2012
- Article first published online: 27 MAR 2012
- Accepted manuscript online: 27 OCT 2011 03:06PM EST
- Manuscript Accepted: 20 OCT 2011
- Manuscript Received: 25 MAR 2011
- Top Institute Pharma. Grant Number: T1-213-1
Obesity is associated with systemic inflammation and is a risk factor for osteoarthritis (OA) development. We undertook this study to test the hypothesis that metabolic stress–induced inflammation, and not mechanical overload, is responsible for the development of high-fat diet–induced OA in mice.
Human C-reactive protein (CRP)–transgenic mice received a high-fat diet without or with 0.005% (weight/weight) rosuvastatin or 0.018% (w/w) rosiglitazone, 2 different drugs with antiinflammatory properties. Mice fed chow were included as controls. After 42 weeks, mice were killed and histologic OA grading of the knees was performed. To monitor the overall inflammation state, systemic human CRP levels were determined.
Male mice on a high-fat diet had significantly higher OA grades than mice on chow and showed no correlation between OA severity and body weight. In male mice, high-fat diet–induced OA was significantly inhibited by rosuvastatin or rosiglitazone to OA grades observed in control mice. Both treatments resulted in reduced human CRP levels. Furthermore, a positive correlation was found between the relative individual induction of human CRP evoked by a high-fat diet on day 3 and OA grade at end point.
High-fat diet–induced OA in mice is due to low-grade inflammation and not to mechanical overload, since no relationship between body weight and OA grade was observed. Moreover, the OA process was inhibited to a great extent by treatment with 2 drugs with antiinflammatory properties. The inflammatory response to a metabolic high-fat challenge may predict individual susceptibility to developing OA later in life. The use of statins or peroxisome proliferator–activated receptor γ agonists (e.g., rosiglitazone) could be a strategy for interfering with the progression of OA.