INSULIN-LIKE-GROWTH-FACTOR SYSTEM ABNORMALITIES IN HEPATITIS C-ASSOCIATED OSTEOSCLEROSIS - POTENTIAL INSIGHTS INTO INCREASING BONE MASS IN ADULTS

Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder charac terized by a marked increase in bone mass during adult life. Despite t he rarity of HCAO, understanding the mediator(s) of the skeletal disea se is of great interest. The IGFs-I and -II have potent anabolic effec ts on bone, and alterations in the IGFs and/or IGF-binding proteins (I GFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, I GF-II, IGF-IIE tan IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary (similar to 150 kD) an d binary (similar to 50 kD) complexes was also determined to assess IG F bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an in crease in IGFBP-2 was unique to these patients and was not found in co ntrol 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 s ubjects, bound to IGFBP-3 in the similar to 150-kD complex, which is r etained in the circulation. However, IGF-IIE was predominantly in the similar to 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we f ound that IGF-II enhanced by over threefold IGFBP-2 binding to extrace llular matrix produced by human osteoblasts and that in an extracellul ar matrix-rich environment, the IGF-II/IGFBP-2 complex was as effectiv e as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-I IE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possib le means to increase bone mass in patients with osteoporosis.