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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 ( approximately 150 kD) and binary (approximately 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 approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 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.


S Khosla ... R L Hintz, C A Conover


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Citations to this article in year 2010 (4)

Title and authors Publication Year
Progressive osteosclerosis and visceral calcification after cord blood transplantation
N Asada, S Ishii, K Wakahashi, H Kawano, Y Kawamori, S Nishikawa, K Minagawa, A Okamura, M Shimoyama, Y Katayama, Y Hayashi, T Itoh, M Tanimoto, T Matsui
International Journal of Hematology 2010
The IGF-I regulatory system and its impact on skeletal and energy homeostasis
M Kawai, CJ Rosen
Journal of Cellular Biochemistry 2010
Mature IGF-II prevents the formation of “big” IGF-II/IGFBP-2 complex in the human circulation
Q Qiu, X Yan, M Bell, J Di, BK Tsang, A Gruslin
Growth Hormone & IGF Research 2010
Crosstalks between integrin alpha 5 and IGF2/IGFBP2 signalling trigger human bone marrow-derived mesenchymal stromal osteogenic differentiation
Z Hamidouche, O Fromigué, J Ringe, T Häupl, PJ Marie
BMC cell biology 2010