IGF-I Regulates Osteoprotegerin (OPG) and Receptor Activator of Nuclear Factor-κB Ligand in Vitro and OPG in Vivo

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 stimu...

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Published in:The journal of clinical endocrinology and metabolism 2002-09, Vol.87 (9), p.4273-4279
Main Authors: Rubin, J, Ackert-Bicknell, C. L, Zhu, L, Fan, X, Murphy, T. C, Nanes, M. S, Marcus, R, Holloway, L, Beamer, W. G, Rosen, C. J
Format: Article
Language:English
Subjects:
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Skeleton and joints
Vertebrates: osteoarticular system, musculoskeletal system
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Summary: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-κB (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 μg/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 μg/liter (∼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 μg/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 μg/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.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2002-020656