Effect of alterations in the cyclopentane ring on bone resorptive activity of prostaglandin

Previous studies have shown that the natural prostanoids, PGE2, PGE1 and PGF2α are potent stimulators of bone resorption. In this study, we have examined the effects of alterations in the cyclopentane ring of these prostanoids for their effect on the resorptive response of cultured long bones from 19-day fetal rats as measured by the release of previously incorporated 45Ca. Indomethacin (10−6M) was added to minimize endogenous prostaglandin production. In this system PGE2 and PGE1, the 9 keto, 11α hydroxy compounds, were approximately equally effective at concentrations of 10−8 to 10−6M. The 9α hydroxy, 11α hydroxy compound, PGF2α, was active at 10−7 to 10−5 M. in contrast, the 9α hydroxy, 11-keto compound, PGD2, showed only a minimal stimulation of bone resorption at 10−5M. While these data suggested that the 11α hydroxy group was important for bone resorbing activity, 11β PGE2 and 11=deoxy PGE1 were only slightly less potent than their physiologic counterparts. Both 9β, 11α PGF2 and 9α, 11β PGF2 were less potent than PGF2α but did cause substantial stimulation of bone resorption and were equally effective at 10−6 to 10−5 M. 9α, 11β PGF2α is of particular interest since it is a major metabolite of PGD2. These results suggest that the binding of prostanoids to the receptor which mediates bone resorption is affected by changes at the 9 and 11 positions of the pentane ring but do not support the hypothesis that the 11α OH function is essential for this biological activity.