title: Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis.
abstract: Elevated serum levels of insulin-like growth factor binding protein-2 (IGFBP-2) and a precursor form of IGF-II are associated with marked increases in bone formation and skeletal mass in patients with hepatitis C-associated osteosclerosis. In vitro studies indicate that IGF-II in complex with IGFBP-2 has high affinity for bone matrix and is able to stimulate osteoblast proliferation. The purpose of this study was to determine the ability of the IGF-II/IGFBP-2 complex to increase bone mass in vivo. Osteopenia of the femur was induced by unilateral sciatic neurectomy in rats. At the time of surgery, 14-day osmotic minipumps containing vehicle or 2 microg IGF-II+9 microg IGFBP-2/100g body weight/day were implanted subcutaneously in the neck. Bone mineral density (BMD) measurements were taken the day of surgery and 14 days later using a PIXImus small animal densitometer. Neurectomy of the right hindlimb resulted in a 9% decrease in right femur BMD (P<0.05 vs. baseline). This loss in BMD was completely prevented by treatment with IGF-II/IGFBP-2. On the control limb, there was no loss of BMD over the 14 days and IGF-II/IGFBP-2 treatment resulted in a 9% increase in left femur BMD (P<0.05). Bone histomorphometry indicated increases in endocortical and cancellous bone formation rates and in trabecular thickness. These results demonstrate that short-term administration of the IGF-II/IGFBP-2 complex can prevent loss of BMD associated with disuse osteoporosis and stimulate bone formation in adult rats. Furthermore, they provide proof of concept for a novel anabolic approach to increasing bone mass in humans with osteoporosis.
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. conover.cheryl@mayo.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Conover
authors.forename: Edward W
authors.initials: EW
authors.lastname: Johnstone
authors.forename: Russell T
authors.initials: RT
authors.lastname: Turner
authors.forename: Glenda L
authors.initials: GL
authors.lastname: Evans
authors.forename: F John
authors.initials: FJ
authors.lastname: John Ballard
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Doran
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects*; D004195:Disease Models, Animal; D004343:Drug Implants; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000008:administration & dosage*; D007335:Insulin-Like Growth Factor II / Q000008:administration & dosage*; D010012:Osteogenesis / Q000187:drug effects*; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D001786:Blood Glucose; D004343:Drug Implants; D018971:Insulin-Like Growth Factor Binding Protein 2; D011994:Recombinant Proteins; D007335:Insulin-Like Growth Factor II
keywords: NASA Discipline Regulatory Physiology; Non-NASA Center