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Rheumatology Advance Access originally published online on January 7, 2009
Rheumatology 2009 48(3):227-232; doi:10.1093/rheumatology/ken462
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway

S. Okazaki1,2, Y. Nishitani2, S. Nagoya1, M. Kaya1, T. Yamashita1 and H. Matsumoto2

1Department of Orthopedic Surgery and 2Department of Legal Medicine and Molecular Alcohology, Sapporo Medical University School of Medicine, Sapporo, Japan.

Correspondence to: H. Matsumoto, Department of Legal Medicine and Molecular Alcohology, Sapporo Medical University School of Medicine, S-1 W-17, Sapporo 060-8556, Japan. E-mail: hmatsumo{at}sapmed.ac.jp


  Abstract

Objectives. Osteonecrosis of the femoral head is observed in patients treated with steroids. However, the pathogenesis of femoral head osteonecrosis remains unclear. We established a rat model with femoral head osteonecrosis by injecting lipopolysaccharide (LPS) and steroid, and assessed the consequences of this on femoral head histology, the systemic immune response and lipid synthesis.

Methods. Male Wistar rats were injected intravenously on days 0 and 1 with 2 mg/kg LPS and intramuscularly with 20 mg/kg methylprednisolone on days 3, 4 and 5. The animals were sacrificed 1, 2, 3 or 4 weeks after the last methylprednisolone injection. Histopathological and biochemical analyses were performed every week.

Results. Osteonecrosis of the femoral head was observed in the rats. The plasma triglyceride concentrations had decreased significantly by weeks 2 and 3. The total plasma cholesterol concentrations had increased significantly by week 1 but then decreased significantly by week 4. The plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-{gamma} and TNF-{alpha} had increased significantly by week 1. These cytokines can all be induced by toll-like receptor 4 (TLR4) signalling.

Conclusions. LPS and methylprednisolone induced osteonecrosis of the femoral head in rats and this was associated with a disruption of the innate immune system and lipid synthesis. These findings suggest that the TLR4 signalling pathway plays an important role in the pathogenesis of femoral head osteonecrosis.

KEY WORDS: Osteonecrosis, Femoral head, Steroid, Lipopolysaccharide, Rat

Submitted 10 February 2007; revised version accepted 19 November 2008.
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