Evaluation of IGF system component levels and mitogenic activity of uremic serum on normal human osteoblasts

To test the hypothesis that impairment in bone formation in renal osteodystrophy in adults with chronic renal failure (CRF) might be mediated in part by alterations in circulating levels of the insulin-like growth factor (IGF) system components, we compared serum levels of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, IGFBP-4 and IGFBP-5 in adults with CRF (CRF patients with parathyroid hormone (PTH) < 100 pg/ml, PTH > 300 pg/ml and end-stage renal failure (ESRF) patients) versus age-matched controls. To evaluate the biological significance of alterations in circulating level of IGF system components, we compared the mitogenic activity of the sera on proliferation of normal human osteoblasts in vitro by using [(3)H]thymidine incorporation. We found severalfold increased serum levels of IGFBP-3 (2-fold), IGFBP-4 (5-fold) and slightly increased IGF-II levels in ESRF patients as well as a 2.6-fold increase in free IGF-I in CRF patients with PTH < 100 pg/ml. The mitogenic activity was found to be increased in serum of kidney failure patients compared to controls. This was most pronounced in CRF patients with PTH < 100 pg/ml showing also a significant increase in free IGF-I and the lowest levels of the IGF-inhibitory IGFBP-4. Our data support the hypothesis that alterations in serum levels of stimulating (i.e. free IGF-I) and inhibitory IGF system components (i.e. IGFBP-4) may influence osteoblastic cell proliferation in renal osteodystrophy.