Both N- and C-terminal domains of parathyroid hormone-related protein increase interleukin-6 by nuclear factor-kappa B activation in osteoblastic cells.
Parathyroid hormone (PTH)-related protein (PTHrP) seems to affect bone resorption by interaction with bone cytokines, among them interleukin-6 (IL-6). Recent studies suggest that nuclear factor (NF)-kappaB activation has an important role in bone resorption. We assessed whether the N-terminal fragment of PTHrP, and its C-terminal region, unrelated to PTH, can activate NF-kappaB, and its relationship with IL-6 gene induction in different rat and human osteoblastic cell preparations. Here we present molecular data demonstrating that both PTHrP (1-36) and PTHrP (107-139) activate NF-kappaB, leading to an increase in IL-6 mRNA, in these cells. Using anti-p65 and anti-p50 antibodies, we detected the presence of both proteins in the activated NF-kappaB complex. This effect induced by either the N- or C-terminal PTHrP domain in osteoblastic cells appears to occur by different intracellular mechanisms, involving protein kinase A or intracellular Ca(2+)/protein kinase C activation, respectively. However, the effect of each peptide alone did not increase further when added together. Our findings lend support to the hypothesis that the C-terminal domain of PTHrP, in a manner similar to its N-terminal fragment, might stimulate bone resorption. These studies also provide further insights into the putative role of PTHrP as a modulator of bone remodeling.
Guillén
Carlos
C
Bone and Mineral Metabolism Laboratory, Research Unit, Fundación Jiménez Díaz, 28040 Madrid, Spain.
Martínez
Pilar
P
de Gortázar
Arancha R
AR
Martínez
María Eugenia
ME
Esbrit
Pedro
P
D001483:Base Sequence; D002460:Cell Line; D016384:Consensus Sequence; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D007700:Kinetics; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; C079957:parathyroid hormone-related peptide (1-36); C071097:parathyroid hormone-related protein (107-139); D000242:Cyclic AMP