The mechanism by which IGFBP-5 exerts anabolic effects in bone

Abstract

To the Editor: In reference to our article in the February issue of Kidney International[1Jehle P.M. Ostertag A. Schulten K. Schulz W. Jehle D.R. Stracke S. Fiedler R. Deuber H.J. Keller F. Boehm B.O. Baylink D.J. Mohan S. Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy.Kidney Int. 2000; 57: 423-436Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], we would like to briefly discuss the mechanism by which insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) might exert its anabolic effects on bone. Human osteoblast-derived IGFBP-5 has been shown to stimulate both proliferation and differentiation of osteoblasts in serum-free cultures[2Andress D.L. Birnbaum R.S. Human osteoblast-derived insulin-like growth factor (IGF) binding protein-5 stimulates osteoblast mitogenesis and potentiates IGF action.J Biol Chem. 1992; 267: 22467-22472Abstract Full Text PDF PubMed Google Scholar, 3Richman C. Baylink D.J. Lang K. Dony C. Mohan S. Recombinant human insulin-like growth factor binding protein-5 stimulates bone formation parameters in vitro and in vivo.Endocrinology. 1999; 140: 4699-4705Crossref PubMed Scopus (109) Google Scholar]. In addition, it has been shown that IGFBP-5 may exert its effects on osteoblasts in part by an IGF-independent mechanism. The significance of an IGF-independent stimulatory pathway for IGFBP-5 action was further underlined by a recent study identifying a putative IGFBP-5 receptor on osteoblasts that appears to function as a serine kinase[4Andress D.L. Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates phosphorylation of the IGFBP-5 receptor.Am J Physiol. 1998; 274: E744-E750PubMed Google Scholar]. Partial purification of the 420 kD protein showed that this is not a proteoglycan and that its phosphorylation on serine residues is stimulated by intact IGFBP-5, IGFBP-5 (1-169) and IGFBP-5 (201-218), but not by IGF-I or transforming growth factor-β (TGF-β). In addition, IGFBP-5 contains a nuclear localization sequence, and recent studies demonstrate evidence for nuclear uptake of fluorescently labeled IGFBP-5 in T47D human breast carcinoma cells[5Schedelich L.J. Young T.F. Firth S.M. Baxter R.C. Insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells.J Biol Chem. 1998; 273: 18347-18352Crossref PubMed Scopus (225) Google Scholar]. Further studies are needed to evaluate the involvement of putative IGFBP-5 receptor and/or nuclear localization sequence in IGFBP-5 in mediating IGF-independent effects on osteoblasts.