ApoE-/-Fas-/-C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis and osteopenia

Xuebing Feng, Hongyun Li, Alexis A. Rumbin, Xuping Wang, Antonio La Cava, Katherine Brechtelsbauer, Lawrence W. Castellani, Joseph L. Witztum, Aldons J. Lusis, and Betty P. Tsao

Rheumatology, UCLA, Los Angeles, CA 90095-1670

Corresponding Author: btsao{at}mednet.ucla.edu

To establish a mouse model of accelerated atherosclerosis in lupus, we generated apolipoprotein E deficient (apoE-/-) and Fas lpr/lpr (Fas-/-) C57BL/6 mice. On a normal chow diet, 5-month-old apoE-/-Fas-/- mice had enlarged glomerular tuft areas, severe proteinuria, elevated circulating autoantibody levels, increased apoptotic cells in renal and vascular lesions compared to either single knockout mice. Also, double knockout mice developed increased atherosclerotic lesions, but decreased serum levels of total and non-high density lipoprotein cholesterol compared to apoE-/-Fas+/+ littermates. Moreover, female apoE-/-Fas-/- mice had lower vertebral BMD and bone volume density (BV/TV) than age-matched female apoE-/-Fas+/+ mice. Compared to apoE-/-Fas+/+ and apoE+/+Fas-/- mice, apoE-/-Fas-/- mice had decreased circulating oxPL content on apoB-100 containing lipoprotein particles, and increased serum IgG antibodies to oxPL which were significantly correlated with aortic lesion areas (r = 0.58), glomerular tuft areas (r = 0.87), BMD (r = -0.57) and BV/TV (r = -0.72). These results suggest that apoE-/-Fas-/- mice model might be used to study atherosclerosis and osteopenia in lupus. Correlations of IgG anti-oxPL with lupus-like disease, atherosclerosis and bone loss suggested a shared pathway of these disease processes.

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