Background/Purpose:

Patients with rheumatoid arthritis (RA) carry a higher risk of cardiovascular disease compared to the general population.  The low-density lipoprotein receptor (LDLR) and Apolipoprotein E (ApoE) have been shown to modulate atherosclerosis in mice, yet murine models of RA-like disease have yielded conflicting data regarding the development of joint disease in mice lacking ApoE.  Here, we examined the effect of deleting ApoE or the LDLR on the development of the effector phase of RA-like disease and on the formation of atherosclerotic lesions in arthritic mice. 

Methods:

The K/BxN serum transfer-induced arthritis (STIA) model was utilized in control, LDLR^-/-, and ApoE^-/-mice.  Inflammatory arthritis severity was assessed using clinical indices and by immunohistochemical staining of ankle joint specimens.  Serum cholesterol levels were determined via enzymatic assays.  Serum cytokine and chemokine levels were measured utilizing luminex-based assays.  Aortic atherosclerotic plaque burden was quantitated using Sudan IV staining.

Results:

LDLR-deficiency resulted in a reduction in arthritis severity as compared to controls.  In contrast, ApoE deficiency had no effect on arthritis intensity.  LDLR^-/- and ApoE^-/- mice exhibited comparable serum levels of total, low-density lipoprotein, and high-density lipoprotein cholesterol.  However, LDLR^-/- STIA mice expressed lower levels of circulating IL-6 compared to ApoE^-/- STIA mice, which correlated with diminished arthritis severity.  Arthritic LDLR^-/- and ApoE^-/-mice displayed a similar degree of aortic atherosclerosis.

Conclusion:

STIA was reduced in LDLR^-/- mice but not ApoE^-/- mice despite similar serum cholesterol profiles in these animals.  These data suggest that factors other than altered cholesterol levels are responsible for the decreased arthritis severity observed in LDLR^-/- mice.  In contrast, atherosclerotic burden was unaffected by the presence of arthritis in either ApoE^-/- or LDLR^-/- mice.  Thus, targeting the LDLR may be a viable strategy to reduce arthritis disease activity in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-density-lipoprotein-receptor-deficiency-ameliorates-the-development-of-inflammatory-arthritis/