The long term objective is to decrease the incidence of fractures in elderly patients with postmenopausal (type 1) or aging (type 2) osteophorosis. This will be achieved by gaining a better basic understanding of how growth factors effect bone formation and their relationship to age-related bone loss. The project will investigate the insulin-like growth factors (which are also called somatomedins because they mediate the growth-promoting effect of growth hormone). The insulin-like growth factors (IGFs) are potent cellular mitogens that directly stimulate bone growth. The rationale for studying IGFs is because they are presently the only hormones known that can produce a graded growth-response in bone, and the plasma level of IGFs and sensitivity of other mesenchymal tissues to IGFs decrease with aging. The in vivo studies will use the perfused rat hind limb as a model to achieve local as opposed to systemic biologic action of the hormones under investigation. IGFs alone and in combination with other calcium regulating hormones (1,25(OH)2D3, PTH, cortisol and GH) will be continually infused by Osmotic Minipumps into the femoral artery of adult and aging rats for 7 to 14 days. Normal, calcium deficient, and partially vitamin D deficient rats will be used. The effects of these manipulations on bone growth as a function of age will be measured by histomorphologic techniques that include double tetracycline labeling. The uninfused side will serve as the control. The systemic level of test hormones will be determined by radioimmunoassays and competitive binding assays. The possibility that other hormones in addition to cortisol affect osteoblast function(s) by modulating IGF receptor status will be investigated using cultured chick osteoblasts in serum free medium. IGF receptor types 1 and 2 will be determined by the specific binding of iodinated IGF-I and -II, and the pattern of competitive binding with IGF-I, IGF-II and insulin. Receptors will be characterized by classic Scatchard analysis. The effect of PTH, calcitriol, 24,(25)OH2,D3, cortisol, and GH on IGF receptors will be correlated with their actions on IGF-stimulated DNA, collagen and noncollagen protein synthesis.
|Spencer, E M; Liu, C C; Si, E C et al. (1991) In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats. Bone 12:21-6|
|Spencer, E M; Si, E C; Liu, C C et al. (1989) Parathyroid hormone potentiates the effect of insulin-like growth factor-I on bone formation. Acta Endocrinol (Copenh) 121:435-42|
|Halloran, B P; Spencer, E M (1988) Dietary phosphorus and 1,25-dihydroxyvitamin D metabolism: influence of insulin-like growth factor I. Endocrinology 123:1225-9|