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


BACKGROUND
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.


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.
Fowlkes
John L
JL
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA. fowlkesjohnl@uams.edu
Thrailkill
Kathryn M
KM
Liu
Lichu
L
Wahl
Elizabeth C
EC
Bunn
Robert C
RC
Cockrell
Gael E
GE
Perrien
Daniel S
DS
Aronson
James
J
Lumpkin
Charles K
CK
D000375:Aging / Q000187:drug effects*; D000818:Animals; D004577:Electron Probe Microanalysis; D006801:Humans; D015552:Injections, Intralesional / Q000295:instrumentation / Q000379:methods*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D008954:Models, Biological; D010012:Osteogenesis / Q000187:drug effects*; D010027:Osteotomy / Q000534:rehabilitation; D011859:Radiography; D011994:Recombinant Proteins / Q000008:administration & dosage*; D013977:Tibia / Q000166:cytology / Q000000981:diagnostic imaging
D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I