Insulin-like growth factor system abnormalities in hepatitis C- associated osteosclerosis. Potential insights into increasing bone mass in adults

Sundeep Khosla, Ahmed A.K. Hassoun, Bonita K. Baker, Frances Liu, Nizar N. Zein, Michael P. Whyte, Charles A. Reasner, Todd B. Nippoldt, Robert D. Tiegs, Raymond L. Hintz, Cheryl A. Conover

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82 Scopus citations

Abstract

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary (~ 150 kD) and binary (~ 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF- I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the ~ 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the ~ 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix 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. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF- IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.

Original languageEnglish (US)
Pages (from-to)2165-2173
Number of pages9
JournalJournal of Clinical Investigation
Volume101
Issue number10
DOIs
StatePublished - May 15 1998

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Keywords

  • Bone formation
  • Dense bones
  • IGF-IIE peptide
  • IGFBP-2
  • Osteoporosis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Khosla, S., Hassoun, A. A. K., Baker, B. K., Liu, F., Zein, N. N., Whyte, M. P., Reasner, C. A., Nippoldt, T. B., Tiegs, R. D., Hintz, R. L., & Conover, C. A. (1998). Insulin-like growth factor system abnormalities in hepatitis C- associated osteosclerosis. Potential insights into increasing bone mass in adults. Journal of Clinical Investigation, 101(10), 2165-2173. https://doi.org/10.1172/JCI1111