Insulin-Like Growth Factor (IGF)-II/IGF-Binding Proteins in Constitutionally Tall Children

Sundeep Khosla and Cheryl A. Conover

Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence to: Sundeep Khosla, M.D., Endocrine Research Unit, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905.

To the editor:

In a recent issue of JCEM, Garrone et al. (1) examine possible changes in the IGF/IGF-binding protein (IGFBP) system in prepubertal children with constitutionally tall stature (CTS) as compared with control children. They report that the CTS and control children have similar IGF-I, IGFBP-3, and acid labile subunit levels, whereas levels of IGF-II and IGFBP-2 are increased (by approximately 66% and 49%, respectively) and those of IGFBP-1 are decreased (by 61%) in the CTS vs. the control children. They also find that the ratio of IGFs to IGFBPs is increased in the CTS children relative to controls and speculate that this may lead to a greater availability of free IGFs for target tissues and, thus, may be responsible for the increased height in CTS children.

These findings are of considerable interest to us in the context of our previous work on changes in the IGF/IGFBP system in patients with hepatitis C-associated osteosclerosis (HCAO; Ref. 2). This is a rare, but now recognized, syndrome of marked increases in bone mass in patients with chronic hepatitis C infection (3, 4, 5, 6, 7, 8, 9). Biochemically and histologically, bone formation indices are markedly increased, although these changes may wane over time once the osteosclerosis is established. In detailed studies on the IGF/IGFBP system (2), we demonstrated that HCAO patients had normal levels of IGF-I and -II but had markedly elevated levels of the IGF-II precursor IGF-IIE. In addition, circulating levels of IGFBP-1, -3, or acid labile subunit were similar to those of control subjects, but levels of IGFBP-2 were significantly elevated. We also demonstrated that IGF-IIE and IGFBP-2 circulated together in a ~50 kD complex, which can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced, by over 3-fold, IGFBP-2 binding to extracellular matrix proteins produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Based on these findings, we proposed that IGFBP-2 may facilitate the targeting of IGFs and, in particular, IGF-IIE and/or IGF-II (because IGF-II also binds IGFBP-2) to skeletal tissues in HCAO patients, with a subsequent stimulation of osteoblast proliferation and activity.

Interestingly, Aria et al. (10) have also shown that the IGF/IGFBP-2 complex has a particular affinity for glycosaminoglycans, which are abundant in the bone matrix (11). Because glycosaminoglycans are also a major constituent of the chondrocyte extracellular matrix (11), our findings in the HCAO patients and the new findings of Garrone et al. (1) suggest that the osteosclerosis in HCAO patients and the increased height velocity in CTS children may, in fact, be due to a very similar underlying mechanism. Thus, in the context of our findings, increases in circulating IGF-II and IGFBP-2 may well result in the formation of a similar IGF-II/IGFBP-2 complex in the circulation of CTS children, with subsequent targeting of the complex, in this case to the growth plate, leading to direct IGF-II effects on chondrocytes. Indeed, because pathology (i.e. CTS) often represents an exaggeration of a normal physiological process, it is possible that the IGF-II/IGFBP-2 complex serves, in fact, to maintain longitudinal growth in normal prepubertal children, before the onset of the rise in GH and IGF-I production at the time of puberty. If so, it is entirely possible that children with constitutionally short stature have low IGF-II and IGFBP-2 levels, and this possibility should be explored.

This hypothesis is attractive, because it also predicts that the excess IGF-II in CTS children would be targeted to skeletal tissues. The problem with hypothesizing a general increase in IGF bioavailability [as proposed by Garrone et al. (1)] is that this should result in other signs of IGF excess in CTS children (e.g. hypoglycemia), which is apparently not the case. Indeed, based on our formulation, another prediction would be that CTS children may, in fact, have a higher bone density than control subjects, even adjusting for differences in bone size. Moreover, because the CTS children likely have bigger bones than controls (not just in length, but also in cross-sectional area), the increased bone size in these children may also be a result of the increase in IGF-II/IGFBP2 driving periosteal bone apposition in the CTS children. These are questions that Garrone et al. (1) can perhaps address in their cohort.

Received December 30, 2002.

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. Villareal DT, Murphy WA, Teitelbaum SL, Arens MQ, Whyte MP 1992 Painful diffuse osteosclerosis after intravenous drug abuse. Am J Med 93:371–381[Medline]
  4. Beyer SH, Parfitt AM, Shih MS, Anderson Q, Heath H III 1990 Idiopathic acquired diffuse osteosclerosis in a young woman. J Bone Miner Res 5:1257–1263[Medline]
  5. Whyte MP, Teitelbaum SL, Reinus WR 1996 Doubling skeletal mass during adult life: the syndrome of diffuse osteosclerosis after intravenous drug abuse. J Bone Miner Res 11:554–558[Medline]
  6. Whyte MP, Reasner CA 1997 Hepatitis C-associated osteosclerosis after blood transfusion. Am J Med 102:219–220[CrossRef][Medline]
  7. Hassoun A, Nippoldt TB, Tiegs RD, Khosla S 1997 Hepatitis C-associated osteosclerosis: an unusual syndrome of acquired osteosclerosis in adults. Am J Med 103:70–73[Medline]
  8. Diamond T, Depczynski B 1996 Acquired osteosclerosis associated with intravenous drug use and hepatitis C infection. Bone 19:679–683[CrossRef][Medline]
  9. Shaker JL, Reinus WR, Whyte MP 1998 Hepatitis C-associated osteosclerosis: late onset after blood transfusion in an elderly woman. J Clin Endocrinol Metab 83:93–98[Abstract/Free Full Text]
  10. Aria T, Busby WJ, Clemmons DR 1996 Binding of insulin-like growth factor (IGF) I or II to IGF-binding rotein-2 enables it to bind heparin and extracellular matrix. Endocrinology 137:4571–4575[Abstract]
  11. Robey PG 2002 Bone marix proteoglycans and glycoproteins. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. San Diego: Academic Press; 225–237




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