PMID- 16394173 OWN - NLM STAT- MEDLINE DCOM- 20060314 LR - 20220408 IS - 0022-0795 (Print) IS - 0022-0795 (Linking) VI - 188 IP - 1 DP - 2006 Jan TI - Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a. PG - 37-47 AB - Recent studies demonstrate widespread expression of ghrelin among tissues and have uncovered its pleiotropic nature. We have examined gene expression of ghrelin and its two receptor splice variants, growth hormone secretagogue receptors (GHS-R) 1a and 1b, in human bone biopsies and in the human pre-osteoblastic SV-HFO cell line during differentiation. Additionally, we examined proliferative effects of ghrelin and unacylated ghrelin (UAG) in differentiating and non-differentiating cells. We detected GHS-R1b mRNA in human bone and osteoblasts but not ghrelin's cognate receptor GHS-R1a, using two different real-time PCR assays and both total RNA and mRNA. In osteoblasts GHS-R1b mRNA expression remained low during the first 14 days of culture, but increased 300% in differentiating cells by day 21. Both human bone biopsies and osteoblasts expressed ghrelin mRNA, and osteoblasts were found to secrete ghrelin. Overall, ghrelin gene expression was greater in differentiating than non-differentiating osteoblasts, but was not increased during culture in either group. Ghrelin and UAG induced thymidine uptake dose-dependently, peaking at 1 and 10 nM respectively, at day 6 of culture in both non-differentiating and differentiating osteoblasts. The proliferative response to ghrelin and UAG declined with culture time and state of differentiation. The proliferative effects of ghrelin and UAG were suppressed by inhibitors of extracellular-signal-regulated kinase (ERK) and phosphoinositide-3 kinase, and both peptides rapidly induced ERK phosphorylation. Overall, our data suggest new roles for ghrelin and UAG in modulating human osteoblast proliferation via a novel signal transduction pathway. FAU - Delhanty, P J D AU - Delhanty PJ AD - Department of Internal Medicine, Erasmus Medical Centre, Dr Molewaterplein 50, 3015 GD Rotterdam, The Netherlands. FAU - van der Eerden, B C J AU - van der Eerden BC FAU - van der Velde, M AU - van der Velde M FAU - Gauna, C AU - Gauna C FAU - Pols, H A P AU - Pols HA FAU - Jahr, H AU - Jahr H FAU - Chiba, H AU - Chiba H FAU - van der Lely, A J AU - van der Lely AJ FAU - van Leeuwen, J P T M AU - van Leeuwen JP LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Endocrinol JT - The Journal of endocrinology JID - 0375363 RN - 0 (Biomarkers) RN - 0 (Ghrelin) RN - 0 (Peptide Hormones) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Receptors, Ghrelin) RN - 9007-49-2 (DNA) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.1.3.1 (Alkaline Phosphatase) RN - VC2W18DGKR (Thymidine) SB - IM MH - Alkaline Phosphatase/metabolism MH - Analysis of Variance MH - Biomarkers/analysis/metabolism MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Cells, Cultured MH - DNA/biosynthesis MH - Femur Head MH - Ghrelin MH - Humans MH - Mitogen-Activated Protein Kinases/*metabolism MH - Osteoblasts/*cytology/drug effects MH - Peptide Hormones/*pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Receptors, G-Protein-Coupled/*metabolism MH - Receptors, Ghrelin MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/*physiology MH - Stimulation, Chemical MH - Thymidine/analysis/metabolism EDAT- 2006/01/06 09:00 MHDA- 2006/03/15 09:00 CRDT- 2006/01/06 09:00 PHST- 2006/01/06 09:00 [pubmed] PHST- 2006/03/15 09:00 [medline] PHST- 2006/01/06 09:00 [entrez] AID - 188/1/37 [pii] AID - 10.1677/joe.1.06404 [doi] PST - ppublish SO - J Endocrinol. 2006 Jan;188(1):37-47. doi: 10.1677/joe.1.06404.