Autocrine control of vitamin D metabolism in synovial cells from arthritic patients

Abstract

Objective - This study was designed to investigate whether 1,25- dihydroxy-vitamin 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.