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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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
StatePublished - May 15 1998

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Osteosclerosis
Insulin-Like Growth Factor II
Somatomedins
Hepatitis C
Insulin-Like Growth Factor Binding Protein 2
Bone and Bones
Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor I
Osteoblasts
Serum
Extracellular Matrix
Anabolic Agents
Insulin-Like Growth Factor Binding Protein 3
Hepatitis B
Protein Binding
Osteogenesis
Biological Availability
Osteoporosis

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Insulin-like growth factor system abnormalities in hepatitis C- associated osteosclerosis. Potential insights into increasing bone mass in adults. / Khosla, Sundeep; Hassoun, Ahmed A K; Baker, Bonita K.; Liu, Frances; Zein, Nizar N.; Whyte, Michael P.; Reasner, Charles A.; Nippoldt, Todd B.; Tiegs, Robert D.; Hintz, Raymond L.; Conover, Cheryl A.

In: Journal of Clinical Investigation, Vol. 101, No. 10, 15.05.1998, p. 2165-2173.

Research output: Contribution to journalArticle

Khosla, S, Hassoun, AAK, Baker, BK, Liu, F, Zein, NN, 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', Journal of Clinical Investigation, vol. 101, no. 10, pp. 2165-2173.
Khosla, Sundeep ; Hassoun, Ahmed A K ; Baker, Bonita K. ; Liu, Frances ; Zein, Nizar N. ; Whyte, Michael P. ; Reasner, Charles A. ; Nippoldt, Todd B. ; Tiegs, Robert D. ; Hintz, Raymond L. ; Conover, Cheryl A. / Insulin-like growth factor system abnormalities in hepatitis C- associated osteosclerosis. Potential insights into increasing bone mass in adults. In: Journal of Clinical Investigation. 1998 ; Vol. 101, No. 10. pp. 2165-2173.
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