Mechanism of regulation of prostaglandin production by parathyroid hormone, interleukin-1, and cortisol in cultured mouse parietal bones.

Bovine PTH-(1-34) (PTH), human recombinant interleukin-1 alpha (IL-1), and cortisol were tested for their effects on bone resorption, prostaglandin (PG) production, and PG endoperoxide synthase (PGH synthase or cyclooxygenase) mRNA levels in cultured mouse parietal bones. Cultures were treated with PTH and IL-1 in the presence and absence of cortisol and arachidonic acid (AA). We found that both PTH and IL-1 stimulated the release of PGE2 and 6-keto-PGF1 alpha (the stable metabolite of PGI2). Stimulation of each metabolite by IL-1 at 0.6-60 pM was 2- to 118-fold, and that by PTH at 24 pM to 24 nM was 3- to 53-fold. Thus, IL-1 was 40-fold more potent than PTH in stimulating PG release. Moreover, IL-1 showed 2- to 3-fold greater efficacy than PTH in stimulating PGE2 release. However, IL-1 was only 4-fold more potent and no more effective than PTH in stimulating 45Ca release. IL-1 (60 pM) and PTH (2.4 nM) stimulation of PGE2 production showed a similar time course, with a lag phase of 0.75-1.5 h. Cortisol (1-100 nM) reduced basal PGE2 production and calcium release. The absolute amounts of PG produced in response to PTH and IL-1 were reduced in the presence of cortisol, but in the presence of AA the relative increases were still from 2.5- to 26-fold compared with levels in cultures treated with cortisol alone. Cortisol reduced the stimulation of 45Ca release by IL-1, but not by PTH. AA (10(-5) M) amplified PG production in response to PTH and IL-1, but not 45Ca release. In bones labeled with [3H]AA, IL-1 and PTH increased [3H]PGE2 and [3H]6-keto-PGF1 alpha release, as measured by HPLC and TLC. IL-1 slightly increased [3H]AA release, but PTH did not. Cortisol decreased [3H]AA release. To test for an effect on PG production at the level of PGH synthase, mRNA levels were measured. mRNA was increased by both PTH and IL-1 to a similar extent despite the greater effect of IL-1 on PGE2 production. Cortisol did not change PGH synthase mRNA levels and did not block the stimulation by PTH or IL-1. We conclude that IL-1 is a more potent stimulator of PG production and bone resorption than PTH. Stimulation of PG production by both PTH and IL-1 is mediated at least in part by increasing PGH synthase, but IL-1 may have an additional effect on AA release.