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

Emory University and Veterans Affairs Medical Center (J.R., L.Z., X.F., T.C.M., M.S.N.), Decatur, Georgia 30033; The Jackson Laboratory (C.L.A.-B., W.G.B., C.J.R.), Bar Harbor, Maine 04609; Maine Center for Osteoporosis Research and Education (W.G.B., C.J.R.), St. Joseph Hospital, Bangor, Maine 04401; and Veterans Affairs Medical Center (R.M., L.H.), Palo Alto, California 94304

Address all correspondence and requests for reprints to: Clifford Rosen, M.D., Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, Bangor, Maine 04401. E-mail: . rofe{at}aol.com

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-B (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.

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