Systemic administration of an anabolic dose of prostaglandin E2 induces early-response genes in rat bones

Systemic administration of prostaglandins of the E series (PGEs) has an anabolic effect in bone. A large part of this osteogenic effect is due to recruitment of osteoblasts from their precursors. However, the immediate events initiated by the administration of an anabolic dose of PGEs or their target cells within bone tissue are not known. In this study we used Northern analysis to explore the induction of early-response genes in bone tissue following a single injection of an anabolic dose of PGE2 (6 mg/kg) and in situ hybridization to localize the responding cells. The mRNA levels of c-fos, c-jun, junB and early growth response gene-1 were markedly elevated in the tibial metaphysis as early as 15 min postinjection and returned to basal level by 180-300 min. The induction of c-fos was the earliest (significant at 15 min) and the greatest (sixfold at 60 min) and that of the other genes was smaller. Early-response gene expression was induced in the calvaria as well. Numerous cells in bone marrow (both in the tibia and calvaria) expressed high levels of c-fos in response to PGE2. In the tibia, these cells were localized in the secondary spongiosa and diaphysis and were absent from the primary spongiosa. Many, but not all, expressing cells were in relative proximity to cancellous or endosteal surfaces. In the calvaria, these cells were found in the marrow "windows" within the bony plate. Mature osteoblasts and osteoclasts were negative. Based on many reports of the stimulation of cancellous bone formation in tibiae of similar animals by PGE2 and the increased bone formation we found in the calvarial marrow spaces, the best candidate for these cells is a bone marrow-resident osteoblast precursor. The induction of early-response genes may thus be the first step in a chain of events which leads to the anabolic effect of PGE2 in vivo.