Insulin-like growth factor I increases bone formation in old or corticosteroid treated rats.

We studied bone induction in subcutaneous implants of demineralized bone matrix with or without insulin-like growth factor I (IGF-I) in aged or corticosteroid-treated rats. Each rat carried one pair of implants, one control and one experiment implant, containing IGF-I dissolved in a hyaluronan solution for slow release. The rats were killed after 3 weeks and the results were evaluated by measuring the calcium content of implants. Young (6-7 weeks) and old (19-27 months) rats were used. A group of young rats was treated for 1 week with subcutaneous injections of 140 micrograms/kg dexamethasone daily. Old rats produced only approximately 1% as much bone as young rats. Local delivery of IGF-I did not increase bone formation in young rats. In old rats, bone formation was increased by IGF-I, 3000 ng/implant. Corticosteroids reduced bone formation in young rats. This effect was partially reversed by local administration of IGF-I.

Expression of insulin-like growth factors during bone induction in rat.

Bone formation was studied after intramuscular implantation of demineralized bone matrix. Ash weight determinations were used to verify the bone-forming ability of implants, and confirmed that no bone was formed when nonactive implants (stripped of their bone-forming ability) were used. A solution hybridization/RNase protection assay was used for the detection of specific mRNA transcripts in the implants and surrounding tissue. Analysis of insulin-like growth factor I (IGF-I) mRNA showed a transient increase peaking on day 3 following implantation. Radioimmunoassay (RIA) for IGF-I-like immunoreactivity indicated a corresponding increase of IGF-I peptide in extracts from the implants at that time point. IGF-II mRNA and alkaline phosphatase mRNA reached highest levels around day 11 following implantation. Bone formation in old rats, 50 weeks of age, was associated with lower IGF-I mRNA levels 3 days after implantation compared with young animals. IGF-II mRNA levels were also affected and tended to be higher 12 days after implantation compared with young animals. These results indicate that IGFs could be paracrine or autocrine factors in the bone-forming process. During this process, IGF-I mRNA is expressed at an early stage, in correlation with the recruitment and proliferation of surrounding mesenchymal cells, whereas IGF-II mRNA is activated significantly later, correlating to the beginning of the actual calcifying process during endochondral bone formation.

Expression of insulin-like growth factor I messenger ribonucleic acid in regenerating bone after fracture: influence of indomethacin.

Expression of insulin-like growth factor I (IGF-I) was studied during time in the callus formed after tibial fracture in rats. Levels of IGF-I mRNA in callus peaked on the day 8 postfracture, showing a 10- to 15-fold induction compared to control bone. Levels of IGF-I mRNA tended also to be increased in the fracture-adjacent musculus tibialis anterior. IGF-I immunoreactivity was found in cartilaginous cells, osteoblasts, and myocytes 6 and 8 days after fracture. No obvious differences were found between hypophysectomized animals and control animals with regard to IGF-I immunoreactivity. Administration of the antiinflammatory drug indomethacin decreased the IGF-I mRNA expression in the tibial fracture model. Previous findings have shown that IGF-I is activated during in vivo muscle regeneration, and also in this model indomethacin administration reduces the expression of IGF-I. The finding that indomethacin administration reduces IGF-I expression could indicate that an inflammatory response may be important for activation of IGF-I during tissue regeneration.

Somatomedins in tumour cyst fluid, cerebrospinal fluid, and tumour cytosol in patients with glial tumours.

In the present study, the levels of the growth-promoting hormones, somatomedins, were analysed in tumour cyst fluid, CSF, and tumour cytosol, collected from 22 unselected patients with intracranial tumours. All samples contained somatomedin activity. 5/7 CSF samples, taken from patients with tumour mass visible on CT, showed elevated concentrations. 6/9 cyst fluid samples, taken from patients with glioma were elevated compared with normal serum somatomedin levels. Tumour cytosol, taken from 7 patients with malignant glioma contained somatomedins in an elevated level compared with values previously analysed from normal adult brains. These preliminary findings demonstrate for the first time the presence of somatomedins in brain tumours and suggest the use of somatomedins as a possible brain tumour marker.

Enhancement of insulin-like growth factor 2 receptors in glioblastoma.

The somatomedins (IGF-1/IGF-2) are a family of growth-promoting hormones which have been identified in the human central nervous system where their specific receptors are distributed. The present study identified somatomedin receptors in glioblastoma and compared them with those found in normal brain. A significant enhancement in the binding of 125I-IGF-2 but not 125I-IGF-1 to glioblastoma membranes was found. A fourfold increase in IGF-2 receptor concentration was observed. These findings indicate enhanced expression of the IGF-2 receptor in glioblastoma.