12213884

pubmed:Citation

9

IGF-I, a ubiquitous polypeptide, plays a key role in longitudinal bone growth and acquisition. The most predominant effect of skeletal IGF-I is acceleration of the differentiation program for osteoblasts. However, in vivo studies using recombinant human (rh) IGF-I and/or rhGH have demonstrated stimulation of both bone formation and resorption, thereby potentially limiting the usefulness of these peptides in the treatment of osteoporosis. In this study, we hypothesized that IGF-I modulates bone resorption by regulating expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) in bone cells. Using Northern analysis in ST2 cells, we found that human IGF-I suppressed OPG mRNA in a time- and dose-dependent manner: 100 micro g/LIGF-I (13 nM) decreased OPG expression by 37.0 +/- 1.8% (P < 0.002). The half maximal inhibitory dose of IGF-I was reached at 50 micro g/liter ( approximately 6.5 nM) with no effect of IGF-I on OPG message stability. Conditioned media from ST2 cells confirmed that IGF-I decreased secreted OPG, reducing levels by 42%, from 12.1-7 ng/ml at 48 h (P < 0.05). Similarly, IGF-I at 100 micro g/liter (13 nM) increased RANKL mRNA expression to 353 +/- 74% above untreated cells as assessed by real-time PCR. In vivo, low doses of rhGH when administered to elderly postmenopausal women only modestly raised serum IGF-I (to concentrations of 18-26 nM) and did not affect circulating OPG concentrations; however, administration of rhIGF-I (30 micro g/kg.d) for 1 yr to older women resulted in a significant increase in serum IGF-I (to concentrations of 39-45 nM) and a 20% reduction in serum OPG (P < 0.05). In summary, we conclude that IGF-I in a dose- and time-dependent manner regulates OPG and RANKL in vitro and in vivo. These data suggest IGF-I may act as a coupling factor in bone remodeling by activating both bone formation and bone resorption; the latter effect appears to be mediated through the OPG/RANKL system in bone.

eng

AIM

MEDLINE

0021-972X

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NLM

4273-9

pubmed-meshheading:12213884-Animals, pubmed-meshheading:12213884-Carrier Proteins, pubmed-meshheading:12213884-Cell Line, pubmed-meshheading:12213884-Gene Expression Regulation, pubmed-meshheading:12213884-Glycoproteins, pubmed-meshheading:12213884-Human Growth Hormone, pubmed-meshheading:12213884-Humans, pubmed-meshheading:12213884-Insulin-Like Growth Factor I, pubmed-meshheading:12213884-Kinetics, pubmed-meshheading:12213884-Membrane Glycoproteins, pubmed-meshheading:12213884-Mice, pubmed-meshheading:12213884-NF-kappa B, pubmed-meshheading:12213884-Osteoprotegerin, pubmed-meshheading:12213884-RANK Ligand, pubmed-meshheading:12213884-RNA, Messenger, pubmed-meshheading:12213884-Receptor Activator of Nuclear Factor-kappa B, pubmed-meshheading:12213884-Receptors, Cytoplasmic and Nuclear, pubmed-meshheading:12213884-Receptors, Tumor Necrosis Factor, pubmed-meshheading:12213884-Recombinant Proteins, pubmed-meshheading:12213884-Stromal Cells, pubmed-meshheading:12213884-Transcription, Genetic

IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S.