Parathyroid hormone-related protein (107-139) stimulates interleukin-6 expression in human osteoblastic cells

The N-terminal region of both parathyroid hormone (PTH) and PTH-related pro tein (PTHrP) binds to the same PTH/PTHrP receptor in osteoblasts. However, C-terminal PTHrP (107-139) inhibits growth and various functions of osteobl asts and osteoclasts apparently through PTHrP-specific receptors. PTH (1-34 ) and PTHrP (1-34) rapidly induce interleukin-6 (IL-6) expression by osteob lasts. The aim of the present study was to assess the effects of PTHrP (107 -139) on IL-6 gene expression and secretion by osteoblastic cells from huma n trabecular bone (hOB). Using reverse transcription followed by PCR, it wa s found that IL-6 mRNA was twofold maximally increased by either PTHrP (1-3 4) or PTHrP (107-139), at 10 nM, over basal within 1 to 2 h in hOB cells. T his effect of PTHrP (107-139), and that of PTHrP (1-34), were abolished by the transcription inhibitor actinomycin D. Meanwhile, puromycin, a protein synthesis inhibitor, superinduced IL-6 expression in the presence or absenc e of each PTHrP peptide. Both PTHrP (1-34) and PTHrP (107-139), but not PTH rP (38-64), stimulated IL-6 secretion to the hOB cell-conditioned medium at 24 h, dose dependently. In addition, this maximal stimulatory effect (twof old over basal) was similar with each PTHrP peptide alone, and not additive when added together. PTHrP (107-139) stimulation of mRNA and protein in hO B cells was abolished by bisindolylmaleimide I, a protein kinase C inhibito r, but not by either adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS), or N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonami de dihydrochloride (H89), two protein kinase A inhibitors. These results in dicate that C-terminal PTHrP, like its N-terminal domain, induces IL-6 prod uction by human osteoblastic cells. This effect of both PTHrP regions could provide a mechanism to modulate bone turnover.