Expression of hypoxia-inducible factor 1alpha by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint.
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 each patient were immunostained for hypoxia-inducible factor 1alpha (HIF-1alpha) and CD68 (a pan-macrophage marker).


RESULTS
HIF-1alpha was expressed abundantly by macrophages in most rheumatoid synovia, predominantly close to the intimal layer but also in the subintimal zone. There was markedly lower expression of HIF-1alpha in OA synovia, and it was absent from all of the healthy synovia.


CONCLUSIONS
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 synovial tissue would result in the transgene being switched on in diseased joints but not in healthy tissues.
Hollander
A P
AP
University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, UK.
Corke
K P
KP
Freemont
A J
AJ
Lewis
C E
CE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007719:Knee Joint / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors