Autocrine control of vitamin D metabolism in synovial cells from arthritic patients.
OBJECTIVE
This study was designed to investigate whether 1, 25-dihydroxyvitamin D3 (1,25-(OH)2D3), produced by activated synovial fluid macrophages, promotes its own catabolism by upregulating vitamin D-24-hydroxylase (24-OHase) in synovial fibroblasts through a vitamin D receptor (VDR) mediated mechanism.


METHODS
Synovial macrophages and fibroblasts were derived from patients with rheumatoid arthritis. Expression of VDR and 24-OHase mRNAs was determined using in situ hybridisation. Vitamin D hydroxylase activity was determined by incubating cells with [3H]-25-(OH)D3, or [3H]-1,25-(OH)2D3, and metabolite synthesis quantified using high performance liquid chromatography.


RESULTS
1, 25-(OH)2D3 increased expression of mRNA for both VDR and 24-OHase in fibroblasts by approximately threefold over 24 hours. 1,25-(OH)2D3 increased fibroblast 24-OHase activity, yielding 24-hydroxylated, and more polar, metabolites. In co-culture, fibroblasts were able to catabolise macrophage derived 1,25-(OH)2D3.


CONCLUSIONS
1, 25-(OH)2D3 is produced by macrophages in vitro at biologically relevant concentrations and can increase its own catabolism by synovial fibroblasts; this effect is probably mediated via upregulation of both synovial fibroblast VDR and 24-OHase.
Smith
S J
SJ
University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL.
Hayes
M E
ME
Selby
P L
PL
Mawer
E B
EB
D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D019898:Autocrine Communication; D002112:Calcifediol / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol