1,25-DIHYDROXYVITAMIN D-3 PRETREATMENT LIMITS PROSTAGLANDIN BIOSYNTHESIS BY CYTOKINE-STIMULATED ADULT HUMAN OSTEOBLAST-LIKE CELLS

The steroid derivative 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) is a regulator of bone biology, and there is evidence that 1,25(OH)(2)D-3 modulates arachidonic acid metabolism in osteoblastic cell model syste ms and in bone organ cultures. In the present studies, 1,25(OH)(2)D-3 decreased prostaglandin (PG) biosynthesis by normal adult human osteob last-like (hOB) cell cultures by about 30%. The decrease was observed under basal incubation conditions, or in specimens stimulated by trans forming growth factor-beta(1) (TGF-beta) or by tumor necrosis factor-a lpha (TNF). The inhibition of the TGF-beta-stimulated PG production ap peared to reflect a diminished efficiency of arachidonic acid conversi on into PGs by the cells, while the efficiency of substrate utilizatio n for PG biosynthesis was unaffected by 1,25(OH)(2)D-3 pretreatment in the unstimulated samples, or in samples stimulated with TNF or with T NF plus TGF-beta. Free arachidonic acid levels were decreased followin g 1,25(OH)(2)D-3 pretreatment in the TNF stimulated samples. hOB cell phospholipase A(2) activity was measured in subcellular fractions, and this activity was decreased by 20-25% in the 1,25(OH)(2)D-3 pretreate d samples. The addition of the selective inhibitor AACOCF(3) to the ph ospholipase A(2) assays provided evidence that it was the cytoplasmic isoform of the enzyme that was affected by the 1,25(OH)(2)D-3 pretreat ment of the hOB cells. Thus, 1,25(OH)(2)D-3 regulation of hOB cell bio logy includes significant effects on arachidonic acid metabolism. In t urn, this could influence the effects of other hormones and cytokines whose actions include the stimulated production of bioactive arachidon ic acid metabolites. (C) 1998 Wiley-Liss, Inc.