Expression of hypoxia-inducible factor la by macrophages in the rheumatoidsynovium - Implications for targeting of therapeutic genes to the inflamedjoint

Objective. To determine if the rheumatoid synovium is a suitable target for hypoxia-regulated gene therapy. Methods. Sequential sections of wax-embedded synovial membrane samples were obtained from 10 patients with rheumatoid arthritis (RA), 10 with primary osteoarthritis (OA), and from 6 healthy, controls. Membrane sections from e ach patient were immunostained for hypoxia-inducible factor 1 alpha (HIF-1 alpha) and CD68 (a pan-macrophage marker). Results. HIF-1 alpha was expressed abundantly by macrophages in most rheuma toid synovia, predominantly close to the intimal layer but also in the subi ntimal zone. There was markedly, lower expression of HIF-1 alpha in OA syno via, and it was absent from all of the healthy synovia. Conclusion. These observations indicate that macrophages transduced with a therapeutic gene under the control of a hypoxia-inducible promoter could be administered to RA patients systemically. Migration of these cells to syno vial tissue would result in the transgene being switched on in diseased joi nts but not in healthy tissues.