title: Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.
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 ( 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.
authors.affiliation: Endocrine Research Unit, Division of Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. Khosla@mayo.edu
authors.forename: S
authors.initials: S
authors.lastname: Khosla
authors.forename: A A
authors.initials: AA
authors.lastname: Hassoun
authors.forename: B K
authors.initials: BK
authors.lastname: Baker
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: N N
authors.initials: NN
authors.lastname: Zein
authors.forename: M P
authors.initials: MP
authors.lastname: Whyte
authors.forename: C A
authors.initials: CA
authors.lastname: Reasner
authors.forename: T B
authors.initials: TB
authors.lastname: Nippoldt
authors.forename: R D
authors.initials: RD
authors.lastname: Tiegs
authors.forename: R L
authors.initials: RL
authors.lastname: Hintz
authors.forename: C A
authors.initials: CA
authors.lastname: Conover
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001682:Biological Availability; D002455:Cell Division / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D006526:Hepatitis C / Q000150:complications*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007335:Insulin-Like Growth Factor II / Q000032:analysis; D010006:Osteoblasts / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000628:therapy; D010026:Osteosclerosis / Q000821:virology*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D013002:Somatomedins / Q000032:analysis*
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D011994:Recombinant Proteins; D013002:Somatomedins; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D001219:Aspartate Aminotransferases; D000469:Alkaline Phosphatase