Author’s Response: Insulin-Like Growth Factor (IGF)-II/IGF-Binding Proteins in Constitutionally Tall Children

Antonina Barreca

Cattedra di Endocrinologia, DiSEM, University of Genova, I-16132 Genova, Italy

Address all correspondence to: Antonina Barreca, M.D., Ph.D., Cattedra di Endocrinologia, DiSEM, University of Genova, Viale Benedetto XV, no 6, I-16132 Genova, Italy. E-mail: barreca{at}unige.it.

To the editor:

We thank Drs. Khosla and Conover for their interest in our study, as it gives us the opportunity to reiterate our conclusions and to compare the data we obtained in constitutionally tall stature (CTS)-affected children with those from hepatitis C-associated osteosclerosis (HCAO) patients (1, 2). Indeed, the osteosclerosis seen in HCAO patients and the increased height velocity in CTS children may be due, with some distinctions, to very similar mechanisms, among which the increased formation of the IGF-II/IGF-binding protein (IGFBP)-2 binary complex might be crucial.

It seems to us that the difference pointed out by Drs. Khosla and Conover is only apparent and that it is due to the fact that we found increased total IGF-II and IGF(I+II)/IGFBPs molar ratio that, although unable to distinguish between the two IGF peptides, is currently considered to be the most accurate indication of the circulating IGF peptides delivered from the ternary and binary complexes. Moreover, although during the last decade an increasing number of publications have reported concentrations of free dissociable IGF-I measured in serum or plasma by a direct immunoradiometric assay, a similar assay for determination of free IGF-II was not available to us. We were, therefore, compelled to refer to free IGF peptide in general. However, our predominant hypothesis—namely that IGF-II, in its free and complexed form with IGFBP-2, is the IGF peptide mainly responsible for overgrowth in CTS—emerges several times in the manuscript, particularly in the Discussion, which focuses almost entirely on this peptide. For example, in keeping with Drs. Khosla and Conover’s interpretation of the data, we stated that "Our study identifies IGF-II as the IGF peptide that may be responsible for overgrowth in CTS children. High circulating levels of IGF-II might be responsible for increased growth velocity, especially in early childhood, when the still immature GH-IGF-I axis has not yet fully assumed its predominant role in body growth"; and that "... IGFBP-2, which shows greater binding affinity for IGF-II, might assume a vicarious role, protecting the peptide from enzymatic degradation and conducting it intact to the target tissue." Another indirect indication that free IGF-II must be greater than free IGF-I, which exerts a stronger inhibitory effect on the pituitary, derives from the lack of GH suppression in our CTS children (1, 3). In this regard, therefore, we seem to be in complete agreement. Moreover, as in their case (2) in which in vitro studies showed that the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation, our interpretation of the results also arose from an in vitro study evaluating the role of the IGF system during osteogenic differentiation in rat tibial osteoblasts in culture (Ref. 4 ; Palermo, C., P. Manduca, E. Gazzerro, L. Foppiani, D. Segat, and A. Barreca, submitted for publication); this demonstrated that IGFBP-2 potentiates endogenous and exogenous (i.e. autocrine/paracrine and endocrine) IGF-II-dependent stimulation of rat osteoblast differentiation in vitro.

One difference between the two studies concerns the age of the population (22 CTS-affected prepubertal subjects aged 2.8–13.3 yr and 7 adult HCAO patients aged 32–73 yr) and, therefore, the circulating concentrations of sex steroids, which are important modulators of bone metabolism (5).

A second difference arises from the molecular form of IGF-II present in circulation [mature 7.4 kDa IGF-II in CTS children; intact IGF-II prohormone (IGF-IIE), in the range of values previously reported for patients with non-islet cell tumor hypoglycemia, in HCAO (2)]. Because numerous data indicate that pro-IGF-II molecules inhibit ternary complex formation for several different reasons (6, 7, 8), the lack of hypoglycemia in our patient population appears less surprising.

Finally, we agree with Drs. Khosla and Conover that other components of the IGF system must be considered in diagnosing growth failure when this condition is unexplained by a defect in any of the more GH-dependent components of the GH-IGF-IGFBP system known to cause it. Following this strategy, years ago we reported a case of short stature associated with high circulating levels of IGFBP-1 and low levels of IGF-II (9).

Received January 21, 2003.

References

  1. Garrone S, Radetti G, Sidoti M, Bozzola M, Minuto F, Barreca A 2002 Increased insulin-like growth factor (IGF)-II and IGF/IGF-binding protein ratio in prepubertal constitutionally tall children. J Clin Endocrinol Metab 87:5455–5460[Abstract/Free Full Text]
  2. Khosla S, Hassoun AAK, Baker BK, Liu F, Zein N, Whyte MP, Reasner CA, Nippoldt TB, Tiegs RD, Hintz RL, Conover CA 1998 Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis: potential insights into increasing bone mass in adults. J Clin Invest 101:2165–2173[Abstract/Free Full Text]
  3. Bozzola M, Radetti G, Buzi F, Tonini G, Moretta A, Autelli M, Aglialoro A, Rondini G, Barreca A 1999 Growth hormone bioactivity and immunoactivity in tall children. J Endocrinol Invest 22:541–546[Medline]
  4. Palermo C, Gazzerro E, Manduca P, Minuto F, Barreca A, Relationship between IGFBP-2 expression and the response to IGF-II of osteoblasts at different stages of differentiation. Proc 4th International Workshop on Insulin-like Growth Factor Binding Proteins, Terrigal, New South Wales, Australia, 2000
  5. Khosla S, Melton III LJ, Atkinson EJ, O’Fallon WM 2001 Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 86:3555–3561[Abstract/Free Full Text]
  6. Zapf J, Futo E, Peter M, Froesch ER 1992 Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest 90:2574–2584[Medline]
  7. Daughaday WH, Trivedi B, Baxter RC 1995 Abnormal serum IGF-II transport in non-islet cell tumor hypoglycemia results from abnormalities of both IGF binding protein-3 and acid labile subunit and leads to elevation of free IGF-II. Endocrine 3:425–430
  8. Daughaday WH 1995 The pathophysiology of IGF-II hypersecretion in non-islet cell tumor hypoglycemia. Diabetes Rev 3:62–72
  9. Barreca A, Bozzola M, Cesarone A, Steenbergh PH, Holthuizen PE, Severi F, Giordano G, Minuto F 1988 Short stature associated with high circulating insulin-like growth factor binding protein-1 (IGFBP-1) and low circulating IGF-II. Effect of GH therapy. J Clin Endocrinol Metab 83:3534–3541




This Article
Full Text (PDF)
Submit a related Letter to the Editor
Purchase Article
View Shopping Cart
Alert me when this article is cited
Alert me when eLetters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Copyright Permission
Google Scholar
Articles by Barreca, A.
Articles citing this Article
PubMed
PubMed Citation
Articles by Barreca, A.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals