Continuous infusion of insulin-like growth factor-I into the epiphysis of the tibia

Abstract

We have developed a method to promote longitudinal bone growth at the level of a specific growth-plate (GP) in young rabbits. Insulin-like growth factor-I (IGF-I) was continuously infused by means of an osmotic pump into the bone marrow cavity of the proximal epiphysis of the tibia. Radiological measurement showed a 2-mm overgrowth of the tibia after 4 weeks of treatment, while histological analysis demonstrated a 15% increase in the thickness of the selected GP. The local infusion of IGF-I increased the numbers of both proliferative and hypertrophic chondrocytes and promoted hyperplasia of bony trabeculae within the epiphysis. The distribution of material infused locally into the epiphysis was simulated by the infusion of Indian ink using the same methodology (osmotic pump) as that for IGF-I. Most of the dye remained within the bone marrow cavity of the epiphysis, but a portion infiltrated into the GP, reaching the deep layer of the physeal chondrocytes and primary spongiosa of the metaphysis. These results suggest that the method reported here is a valid one for delivering cytokines or growth factors to the selected GP and for controlling the growth and differentiation of physeal chondrocytes.

Lengthening of mouse hind limbs with local administration of insulin-like growth factor 2

“…They are reported to be able to recruit primary osteoblastic cells, and regulate proliferation and differentiation of chondrocytes in the growth plate. 9 Our results support the notion that therapeutic administration of IGF2 can enhance longitudinal bone growth in a mature skeletal system in which IGF2 is not considered to be actively utilized.…”

“…9,24 Although the current study reveals that administration of IGF2 also elevates body weight, it is yet to be investigated whether any other side effects associated with IGF2 exist and whether a combinatory administration of IGF1 and IGF2 (and other factors) may minimize adverse effects. 9 We have previously shown using a C28/I2 chondrocyte cell line that administration of IGF2 (5 hours at 10e100 ng/ml) activates TGFb signaling, 19 which stimulates osteoblast development through activation of ERK. 9 Although other pathways such as phosphoinositide 3-kinase signaling are also involved, 25 we evaluated any linkage between administration of IGF2 and the phosphorylation of ERK.…”

“…In the IGF2 group, a total volume of 5 ml phosphate buffered saline (PBS) containing 0.4 mg/ml recombinant IGF2 (R & D systems, Inc., Minneapolis, MN, USA; 792-MG) was injected into the distal epiphyseal region of the left femur using a microsyringe (Hamilton Company, Reno, Nevada, USA) with a #30 gauge needle. 9 In the placebo group, the left epiphysis of the distal femur received a similar amount of saline. Local administration of IGF2 was performed daily for 5 consecutive days with a dosage of 100 mg/kg/day.…”

“…Using C57/BL/6 mice (w 8 weeks), we examined the hypothesis by measuring bone length, bone weight, bone mineral density (BMD), and bone mineral content (BMC) of the femora and tibiae. Since clinical data indicate an increase in body weight following the administration of IGF1, 9 we monitored total body weight before and after the administration of IGF2.…”

“…GH regulates synthesis of IGF1 primarily in the liver. It has been reported that administration of IGF1 is effective in lengthening the tibia in rabbits, 9 although an increased incidence of adrenal medullary hyperplasia and pheochromocytoma was reported. 10 IGF2 is an imprinted gene in both mice and humans, producing a 7.5 kD mature protein consisting of 67 amino acid residues.…”