END-ORGAN RESISTANCE TO GROWTH-HORMONE AND IGF-I IN EPIPHYSEAL CHONDROCYTES OF RATS WITH CHRONIC-RENAL-FAILURE

We tested the hypothesis that there is direct end-organ resistance to growth hormone (GH) and IGF-I in chronic renal failure (CRF) independe nt of circulating inhibitors. Male Sprague-Dawley rats underwent 5/6 n ephrectomy and were pair-fed with weight matched (100 g) sham operated controls fur two weeks. Rats with CRF bad significantly higher serum creatinine and blood urea nitrogen (P < 0.01 in both cases) and gained significantly less weight and length (P < 0.01 in both cases) compare d with controls. Epiphyseal chondrocytes were grown in 10% fetal calf serum (FCS). Both CRF cells and control cells maintained chondrogenic phenotypes, and showed immunohistochemical staining with antibodies to collagen II and proteoglycan (aggrecan). Distribution of the cell sub populations according to cell size (by flow cytometry) and alkaline ph osphatase activity of CRF and control chondrocyte cultures were not di fferent. Growth responses of CRF chondrocytes were reduced (P < 0.01) compared with control chondrocytes when grown in 10% FCS and 10% norma l rat serum. Under serum free conditions, growth responses of CRF chon drocytes were reduced to GH and IGF-I at concentrations of 10, 30, and 100 ng/ml, and to insulin at 100, 300 and 1,000 ng/ml compared with c ontrols cells (P < 0.01). To show that this resistance is specific for the GH/IGF system, growth responses to fibroblast growth factor and t ransforming growth factor beta 1 were studied and showed no difference between CRF and control cells. Thus, the present study provides direc t evidence of specific end-organ resistance to GH, IGF-I in CRF chondr ocytes in the absence of circulating factors.