IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear Factor-κB ligand in vitro and OPG in vivo

被引:131
作者
Rubin, J
Ackert-Bicknell, CL
Zhu, L
Fan, X
Murphy, TC
Nanes, MS
Marcus, R
Holloway, L
Beamer, WG
Rosen, CJ [1 ]
机构
[1] St Joseph Hosp, Maine Ctr Osteoporosis Res & Educ, Bangor, ME 04401 USA
[2] Emory Univ, Decatur, GA 30033 USA
[3] Vet Affairs Med Ctr, Decatur, GA 30033 USA
[4] Jackson Lab, Bar Harbor, ME 04609 USA
[5] Vet Affairs Med Ctr, Palo Alto, CA 94304 USA
关键词
D O I
10.1210/jc.2002-020656
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 mug/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 mug/liter (similar to6.5 rim) 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 mug/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 mug/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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收藏
页码:4273 / 4279
页数:7
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