Serum insulin-like growth factor binding protein-3 in the hypophosphatemic mouse: Decreased activity and abnormal modulation by dietary phosphate

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Abstract
The hypophosphatemic mouse, the murine homologue of X‐linked hypophosphatemia, is characterized by renal defects in phosphate reabsorption and 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3) production and by an osteoblast dysfunction. In view of the potential importance of insulin‐like growth factors (IGFs) in the regulation of these processes and the role of IGF‐binding proteins (IGFBPs) as modulators of IGF action, we asked whether Hyp mice have alterations in IGFs or IGFBPs. Using specific radioimmunoassays and Western ligand blot analysis, we evaluated serum levels of IGFs (IGF‐I and IGF‐II) and IGFBPs, respectively, in normal and Hyp mice. We also examined the effect of dietary phosphate on these parameters. Serum levels of IGF‐I and IGF‐II in Hyp mice were not significantly different from those in normal mice, but IGFBP‐3 levels were significantly lower (70% of normal, p < 0.05) in the mutant strain. The other IGFBP species appear unchanged. Phosphate supplementation normalized serum phosphate levels in Hyp mice and elicited a significant decrease in serum IGF‐I levels (23%, p < 0.05) and a further reduction in IGFBP‐3 (22%, p < 0.02). Phosphate deprivation induced hypophosphatemia in normal mice to a degree similar to that in Hyp mice and did not alter serum levels of IGFBP‐3 and IGF‐I and IGF‐II. The present results indicate that the low serum IGFBP‐3 activity in Hyp mice is not related to hypophosphatemia per se. Based on the documented effects of parathyroid hormone (PTH) on IGF‐I and IGFBP‐3, we propose that the secondary hyperparathyroidism displayed by Hyp mice and its exacerbation by phosphate supplementation may contribute to low IGFBP‐3 levels in control Hyp mice and to the decreases in serum IGF‐I and IGFBP‐3 in phosphate‐supplemented Hyp mice.
Funding Information
  • Shriners of North America and the “Fonds de la Recherche en Santé du Québec (FRSQ).”
  • Annual Meeting of the American Society for Bone and Mineral Research