Effects of prostacyclin and prostaglandin E₁ (PGE₁) on bone resorption in the presence and absence of parathyroid hormone

Summary

Prostaglandins have been shown to stimulate osteoclastic bone resorption in organ culture but morphologic studies of isolated osteoclasts have shown a transient calcitonin-like inhibiting effect of these agents. We looked for a dual effect on bone resorption by comparing the early and late effects of prostaglandin E₁ (PGE₁), prostacyclin (PGI₂), 6α-carbaprostaglandin I₂ (C-PGI₂), a carbon substituted analog of PGI₂, and salmon calcitonin (CT) on the release of previously incorporated⁴⁵Ca from fetal rat long bones cultured in the presence of an inhibitor of cyclooxygenase, RO-20-5720. Experiments were performed in both the presence and absence of PTH (400 ng/ml), which was administered 24 hours before addition of prostaglandins or CT. In control cultures not stimulated by PTH, CT (100 mU/ml) produced significant decreases in⁴⁵Ca release at 48, 72, and 96 hours while PGE₁ (10⁻⁶ M), PGI₂ (10⁻⁵), and C-PGI₂ (10⁻⁶ M) each produced significant increases in resorption at 24 through 96 hours. PGE₁ at 10⁻⁵ M, but not 10⁻⁶ M, caused a significant decrease in medium⁴⁵Ca of 21% at 1 and 2 hours. Medium calcium measurements suggest that the change in⁴⁵Ca was due to inhibition of release and not to increased uptake. PGI₂ (10⁻⁵ M) and C-PGI₂ (10⁻⁶ M) caused no significant inhibitory effect. In cultures stimulated by PTH, CT produced significant inhibition of bone resorption of 6 through 96 hours, but no inhibition of bone resorption was noted at either early or late time points with PGE₁, PGI₂, or C-PGI₂. Moreover, the addition of PGI₂ (10⁻⁵M) to PTH-treated cultures actually enhanced⁴⁵Ca release beginning to 6 hours, when PGI₂ alone had no effect upon bone resorption. These results confirm that high concentration of PGI₂ can stimulate bone resorption and show a similar response to a stable analog, C-PGI₂. Moreover, PGI₂ was found to enhance PTH-stimulated bone resorption. A small transient inhibition of⁴⁵Ca release was observed with a high concentration of PGE₁ (10⁻⁵M) in the absence of PTH, which could be due to a transient direct inhibitory action upon osteoclasts.