Autocrine control of vitamin D metabolism in synovial cells from arthriticpatients

Objective-This study was designed to investigate whether 1,25-dihydroxy-vit amin D-3 (1,25-(OH)(2)D-3), produced by activated synovial fluid macrophage s, promotes its own catabolism by upregulating vitamin D-24-hydroxylase (24 -OHase) in synovial fibroblasts through a vitamin D receptor (VDR) mediated mechanism. Methods-Synovialmacrophages 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 [H-3]-25-(OH)D-3, or [H-3]-1,25-(OH)(2)D-3, and me tabolite synthesis quantified using high performance liquid chromatography. Results-1,25-(OH)(2)D-3 increased expression of mRNA for both VDR and 24-OH ase in fibroblasts by approximately threefold over 24 hours. 1,25-(OH),D, i ncreased fibroblast 24-OHase activity, yielding 24-hydroxylated, and more p olar, metabolites. In co-culture, fibroblasts were able to catabolise macro phage derived 1,25-(OH)(2)D-3. Conclusions-1,25-(OH)(2)D-3 is produced by macrophages in vitro at biologic ally relevant concentrations and can increase its own catabolism by synovia l fibroblasts; this effect is probably mediated via up-regulation of both s ynovial fibroblast VDR and 24-OHase.