Effects of systemic and local administration of recombinant human IGF-I (rhIGF-I) on de novo bone formation in an aged mouse model.

Fowlkes JL, Thrailkill KM, Liu L, Wahl EC, Bunn RC, Cockrell GE, Perrien DS, Aronson J, Lumpkin CK
J Bone Miner Res. 2006 21 (9): 1359-66

PMID: 16939394 · PMCID: PMC2424402 · DOI:10.1359/jbmr.060618

UNLABELLED - DO was used in an aged mouse model to determine if systemically and/or locally administered rhIGF-I improved osteoblastogenesis and new bone formation. Local and systemic rhIGF-I treatment increased new bone formation. However, only systemic delivery produced measurable concentrations of rhIGF-I in the circulation.

INTRODUCTION - Human and rodent research supports a primary role for IGF-I in bone formation. Significant roles for both endocrine and paracrine/autocrine IGF-I have been suggested for normal osteoblastogenesis and bone formation. We have assessed, using a mouse model of distraction osteogenesis (DO), the impact of continuous administration of recombinant human (rh)IGF-I, delivered either locally to the distraction site or absorbed systemically, on bone formation in an aged mouse model.

MATERIALS AND METHODS - DO was performed in aged mice (18-month-old C57BL/6 male mice), which were distracted at 0.15 mm daily. At the time of osteotomy, miniosmotic pumps were inserted subcutaneously to (1) deliver vehicle or rhIGF-I subcutaneously for systemic delivery or (2) deliver vehicle or rhIGF-I directly to the newly forming bone through infusion tubing routed subcutaneously from the pump to the distraction site. Serum concentrations of mouse IGF-I, human IGF-I, and osteocalcin were determined at the end of the study.

RESULTS - New bone formation observed in DO gaps showed a significant increase in new bone formation in rhIGF-I-treated mice, irrespective of delivery route. However, detectable levels of human IGF-I were found only in the serum of animals receiving rhIGF-I systemically. Osteocalcin levels did not differ between controls and rhIGF-I-treated groups.

CONCLUSIONS - Locally and systemically delivered rhIGF-I both produce significant increases in new bone formed in an aged mouse model in which new bone formation is normally markedly impaired, suggesting that rhIGF-I may improve senile osteoporosis. Because systemic administration of IGF-I can result in untoward side effects, including an increased risk for cancer, the findings that locally delivered IGF-I improves bone regeneration without increasing circulating IGF-I levels suggests that this delivery route may be preferable in an at-risk, aged population.

MeSH Terms (16)

Aging Animals Electron Probe Microanalysis Humans Injections, Intralesional Insulin-Like Growth Factor I Male Mice Mice, Inbred C57BL Models, Animal Models, Biological Osteogenesis Osteotomy Radiography Recombinant Proteins Tibia

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