Role of IGF-I as a Potential Mediator for the Skeletal Effects of Bone Anabolic Agents

Growth hormone (GH) has a critical role in the regulation of longitudinal bone growth, skeletal maturation, and maintenance of adult bone mass. Insulin-like growth factor I (IGF-I) is considered the prime mediator for the skeletal effects of GH. Parathyroid hormone (PTH) has potent anabolic effects and its use as an osteoporosis therapy is approved by the Food and Drug Administration. Prostaglandin E2 (PGE₂) can also induce cortical and trabecular bone formation in animal models. The role of IGF-I as a potential mediator for the bone anabolic effects of PTH and PGE₂ is controversial as in vivo and in vitro studies have yielded conflicting results.

The objectives of this study were: 1- Evaluate the dwarf rat (dw^-/dw^-) as an animal model for the effects of GH and IGF-I deficiency on the skeleton, as related to clinical conditions in which serum levels of IGF-I are decreased but not abolished; 2- Compare the skeletal effects of PTH and PGE₂ treatment in dwarf rats and their background strain, Lewis rats; 3- Determine the expression of genes related to bone formation and resorption. At 9 weeks of age, female Lewis and dwarf rats were treated daily for 2 weeks with vehicle, hPTH 1-34 at a dose of 50 µg/kg body weight, or PGE₂ at a dose of 3 mg/kg body weight (N=7-10/group). Serum IGF-I was measured by ELISA, and bone changes were analyzed by histomorphometry, peripheral quantitative computerized tomography (pQCT), and biomechanical testing. RNA was isolated from bone tissue for evaluation of gene expression by RT-PCR.

Dwarf rats exhibited markedly lower IGF-I serum levels, and decreased bone mass, strength, and formation compared to Lewis rats. PTH and PGE₂ treatment increased bone mass and formation in both dwarf and Lewis rats. Sclerostin, a potent negative regulator of bone formation, was downregulated in PTH- and PGE₂-treated dwarf rats, suggesting that sclerostin inhibition could be related to the persistent bone anabolic effects of PTH and PGE₂, despite low IGF-I serum levels in dwarf rats. Therefore, under the conditions of this study, normal serum levels of IGF-I are not essential for the bone anabolic effects of PTH and PGE₂.

Year	Entry
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Year

Entry

2003

Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. May 15, 2003;423(6937):337-342.

2005

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. May 20, 2005;280(20):19883-19887.

2009

Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.

2007

Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell. August 10, 2007;130(3):456-469.

2004

Mullender M, El Haj AJ, Yang Y, van Duin MA, Burger EH, Klein-Nulend J. Mechanotransduction of bone cells in vitro: mechanobiology of bone tissue. Med Biol Eng Comput. January 2004;42(1):14-21.