RRC ID 73038
Author Rubin J, Ackert-Bicknell CL, Zhu L, Fan X, Murphy TC, Nanes MS, Marcus R, Holloway L, Beamer WG, Rosen CJ.
Title IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand in vitro and OPG in vivo.
Journal J Clin Endocrinol Metab
Abstract 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.
Volume 87(9)
Pages 4273-9
Published 2002-9-1
DOI 10.1210/jc.2002-020656
PMID 12213884
MeSH Animals Carrier Proteins / genetics* Cell Line Gene Expression Regulation / drug effects* Glycoproteins / genetics* Human Growth Hormone / pharmacology Humans Insulin-Like Growth Factor I / pharmacology* Kinetics Membrane Glycoproteins / genetics* Mice NF-kappa B / metabolism Osteoprotegerin RANK Ligand RNA, Messenger / genetics Receptor Activator of Nuclear Factor-kappa B Receptors, Cytoplasmic and Nuclear / genetics* Receptors, Tumor Necrosis Factor Recombinant Proteins / pharmacology Stromal Cells / cytology Transcription, Genetic* / drug effects
IF 5.399
Human and Animal Cells ST2(RCB0224)