Rheumatoid arthritis is a painful and debilitating inflammatory disorder with no known cure. It has been hypothesised that targeting the activity of RHO family proteins might be an effective therapeutic strategy, as these proteins are required for the function of macrophages, which contribute to immunopathology in arthritic joints. However, this notion is challenged in a recent paper by Khan et al. Unexpectedly, mice deficient for a key RHO-activating enzyme, geranylgeranyltransferase type I (GGTase-I), specifically in macrophages were found to develop spontaneous and severe joint inflammation resembling erosive rheumatoid arthritis. Macrophage-specific deficiency in GGTase-I was sufficient to induce pro-inflammatory signalling pathways and initiate the disease owing to sustained activation of RHO family proteins in macrophages. These data indicate that GGTase-I is not essential for the activity of RHO family proteins, and that inhibition of this enzyme can worsen, rather than prevent, the progression of rheumatoid arthritis.

Khan O. M., Ibrahim M. X., Jonsson I. M., Karlsson C., Liu M., Sjogren A. K., Olofsson F. J., Brisslert M., Andersson S., Ohlsson C., et al.  (2011). Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice. J. Clin. Invest. 121, 628– 639.
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Written by editorial staff. © 2011. Published by The Company of Biologists Ltd.
2011
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