Intermittent PTH increases trabecular bone mass in vivo by stimulating osteoblast differentiation to increase bone formation. The molecular events that mediate the anabolic effect of PTH on osteoblasts have not been characterized. We investigated if PTH regulated mRNA expression of proto-oncogenes, c-fos, c-jun, and c-myc, early response genes that have been shown to be involved in the regulation of both cell proliferation and differentiation. As PTH also regulates the early expression of the cytokine, interleukin-6 (IL-6), in bone cells in vitro, we also investigated if this occurred in vivo, in concert with the other early response genes. Northern blot hybridization was used to analyze mRNA expression in the metaphysis of the distal femur of young rats. To determine the proliferative state in these femurs, mRNA expression of the cell proliferation marker histone, H4, was assessed. Subcutaneous administration of a single injection of human PTH (1–34) at 8 μg/100 g, a dose known to increase bone forming surfaces, induced rapid and transient expression of c-fos, c-jun, c-myc, and IL-6 mRNA. A second novel transcript for IL-6 was detected, but its significance remains unknown. Induction of all these messages was evident by 1 h; the levels of mRNA returned to baseline after 3–6 h. Concurrently, PTH had a small inhibitory effect on the expression of histone H4 mRNA. We conclude that, in vivo, PTH upregulates cell differentiation in trabecular bone by transient stimulation of the early response genes and IL-6, while downregulating cell proliferation.