• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. May 15, 1998; 101(10): 2165–2173.
PMCID: PMC508804

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.

Full Text

The Full Text of this article is available as a PDF (251K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Villareal DT, Murphy WA, Teitelbaum SL, Arens MQ, Whyte MP. Painful diffuse osteosclerosis after intravenous drug abuse. Am J Med. 1992 Oct;93(4):371–381. [PubMed]
  • Beyer HS, Parfitt AM, Shih MS, Anderson Q, Heath H., 3rd Idiopathic acquired diffuse osteosclerosis in a young woman. J Bone Miner Res. 1990 Dec;5(12):1257–1263. [PubMed]
  • Whyte MP, Teitelbaum SL, Reinus WR. Doubling skeletal mass during adult life: the syndrome of diffuse osteosclerosis after intravenous drug abuse. J Bone Miner Res. 1996 Apr;11(4):554–558. [PubMed]
  • Whyte MP, Reasner CA., 2nd Hepatitis C-associated osteosclerosis after blood transfusion. Am J Med. 1997 Feb;102(2):219–220. [PubMed]
  • Hassoun AA, Nippoldt TB, Tiegs RD, Khosla S. Hepatitis C-associated osteosclerosis: an unusual syndrome of acquired osteosclerosis in adults. Am J Med. 1997 Jul;103(1):70–73. [PubMed]
  • Diamond T, Depczynski B. Acquired osteosclerosis associated with intravenous drug use and hepatitis C infection. Bone. 1996 Dec;19(6):679–683. [PubMed]
  • Bergman D, Einhorn TI, Forster G. Stone bone syndrome--diffuse sclerosis of bone: a newly described clinical disorder. Endocr Pract. 1996 Jul-Aug;2(4):296–296. [PubMed]
  • Shaker JL, Reinus WR, Whyte MP. Hepatitis C-associated osteosclerosis: late onset after blood transfusion in an elderly woman. J Clin Endocrinol Metab. 1998 Jan;83(1):93–98. [PubMed]
  • Beyer HS, Anderson Q, Shih MS, Parfitt AM, Heath H., 3rd Diffuse osteosclerosis in intravenous drug abusers. Am J Med. 1993 Dec;95(6):660–662. [PubMed]
  • Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997 Feb 27;336(9):633–640. [PubMed]
  • Rotwein P. Two insulin-like growth factor I messenger RNAs are expressed in human liver. Proc Natl Acad Sci U S A. 1986 Jan;83(1):77–81. [PMC free article] [PubMed]
  • Bell GI, Merryweather JP, Sanchez-Pescador R, Stempien MM, Priestley L, Scott J, Rall LB. Sequence of a cDNA clone encoding human preproinsulin-like growth factor II. Nature. 310(5980):775–777. [PubMed]
  • Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem. 1978 Apr 25;253(8):2769–2776. [PubMed]
  • Rinderknecht E, Humbel RE. Primary structure of human insulin-like growth factor II. FEBS Lett. 1978 May 15;89(2):283–286. [PubMed]
  • Gowan LK, Hampton B, Hill DJ, Schlueter RJ, Perdue JF. Purification and characterization of a unique high molecular weight form of insulin-like growth factor II. Endocrinology. 1987 Aug;121(2):449–458. [PubMed]
  • Valenzano KJ, Heath-Monnig E, Tollefsen SE, Lake M, Lobel P. Biophysical and biological properties of naturally occurring high molecular weight insulin-like growth factor II variants. J Biol Chem. 1997 Feb 21;272(8):4804–4813. [PubMed]
  • Daughaday WH, Emanuele MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med. 1988 Dec 1;319(22):1434–1440. [PubMed]
  • Zapf J, Futo E, Peter M, Froesch ER. Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest. 1992 Dec;90(6):2574–2584. [PMC free article] [PubMed]
  • Baxter RC. The role of insulin-like growth factors and their binding proteins in tumor hypoglycemia. Horm Res. 1996;46(4-5):195–201. [PubMed]
  • Liu F, Baker BK, Powell DR, Hintz RL. Characterization of proinsulin-like growth factor-II E-region immunoreactivity in serum and other biological fluids. J Clin Endocrinol Metab. 1993 May;76(5):1095–1100. [PubMed]
  • LeRoith D, Clemmons D, Nissley P, Rechler MM. NIH conference. Insulin-like growth factors in health and disease. Ann Intern Med. 1992 May 15;116(10):854–862. [PubMed]
  • Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL. Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uremic serum. J Clin Endocrinol Metab. 1986 Nov;63(5):1186–1192. [PubMed]
  • Liu F, Baxter RC, Hintz RL. Characterization of the high molecular weight insulin-like growth factor complex in term pregnancy serum. J Clin Endocrinol Metab. 1992 Nov;75(5):1261–1267. [PubMed]
  • Hassager C, Fitzpatrick LA, Spencer EM, Riggs BL, Conover CA. Basal and regulated secretion of insulin-like growth factor binding proteins in osteoblast-like cells is cell line specific. J Clin Endocrinol Metab. 1992 Jul;75(1):228–233. [PubMed]
  • Hossenlopp P, Seurin D, Segovia-Quinson B, Hardouin S, Binoux M. Analysis of serum insulin-like growth factor binding proteins using western blotting: use of the method for titration of the binding proteins and competitive binding studies. Anal Biochem. 1986 Apr;154(1):138–143. [PubMed]
  • Robey PG, Termine JD. Human bone cells in vitro. Calcif Tissue Int. 1985 Sep;37(5):453–460. [PubMed]
  • Harris SA, Enger RJ, Riggs BL, Spelsberg TC. Development and characterization of a conditionally immortalized human fetal osteoblastic cell line. J Bone Miner Res. 1995 Feb;10(2):178–186. [PubMed]
  • Arai T, Busby W, Jr, Clemmons DR. Binding of insulin-like growth factor (IGF) I or II to IGF-binding protein-2 enables it to bind to heparin and extracellular matrix. Endocrinology. 1996 Nov;137(11):4571–4575. [PubMed]
  • Conover CA. A unique receptor-independent mechanism by which insulinlike growth factor I regulates the availability of insulinlike growth factor binding proteins in normal and transformed human fibroblasts. J Clin Invest. 1991 Oct;88(4):1354–1361. [PMC free article] [PubMed]
  • Durham SK, Kiefer MC, Riggs BL, Conover CA. Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: implications in bone cell physiology. J Bone Miner Res. 1994 Jan;9(1):111–117. [PubMed]
  • Clemmons DR, Snyder DK, Busby WH., Jr Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects. J Clin Endocrinol Metab. 1991 Oct;73(4):727–733. [PubMed]
  • Mohnike K, Kluba U, Blum WF, Aumann V, Vorwerk P, Mittler U. Serumkonzentrationen der insulinähnlichen Wachstumsfaktoren (IGF)-I und IGF-II sowie der IGF Bindungsproteine (IGFBP)-2 und IGFBP-3 bei 49 Kindern mit ALL, NHL oder soliden Tumoren. Klin Padiatr. 1995 Jul-Aug;207(4):225–229. [PubMed]
  • Scharf JG, Schmitz F, Frystyk J, Skjaerbaek C, Moesus H, Blum WF, Ramadori G, Hartmann H. Insulin-like growth factor-I serum concentrations and patterns of insulin-like growth factor binding proteins in patients with chronic liver disease. J Hepatol. 1996 Nov;25(5):689–699. [PubMed]
  • Tally M, Eriksson U, Thorén M, Brismar K, Hall K. Immunoreactive proinsulin-like growth factor-II levels in healthy subjects, patients with growth hormone deficiency, and patients with type 1 diabetes: effects of insulin-like growth factor-I and insulin. J Clin Endocrinol Metab. 1994 Dec;79(6):1576–1581. [PubMed]
  • Prosser CG, Schwander J. Influence of insulin-like growth factor-binding protein-2 on plasma clearance and transfer of insulin-like growth factors-I and -II from plasma into mammary-derived lymph and milk of goats. J Endocrinol. 1996 Jul;150(1):121–127. [PubMed]
  • Feyen JH, Evans DB, Binkert C, Heinrich GF, Geisse S, Kocher HP. Recombinant human [Cys281]insulin-like growth factor-binding protein 2 inhibits both basal and insulin-like growth factor I-stimulated proliferation and collagen synthesis in fetal rat calvariae. J Biol Chem. 1991 Oct 15;266(29):19469–19474. [PubMed]
  • Raisz LG, Fall PM, Gabbitas BY, McCarthy TL, Kream BE, Canalis E. Effects of prostaglandin E2 on bone formation in cultured fetal rat calvariae: role of insulin-like growth factor-I. Endocrinology. 1993 Oct;133(4):1504–1510. [PubMed]
  • Delany AM, Rydziel S, Canalis E. Autocrine down-regulation of collagenase-3 in rat bone cell cultures by insulin-like growth factors. Endocrinology. 1996 Nov;137(11):4665–4670. [PubMed]
  • Kream BE, Tetradis S, Lafrancis D, Fall PM, Feyen JH, Raisz LG. Modulation of the effects of glucocorticoids on collagen synthesis in fetal rat calvariae by insulin-like growth factor binding protein-2. J Bone Miner Res. 1997 Jun;12(6):889–895. [PubMed]
  • Schmid C, Rutishauser J, Schläpfer I, Froesch ER, Zapf J. Intact but not truncated insulin-like growth factor binding protein-3 (IGFBP-3) blocks IGF I-induced stimulation of osteoblasts: control of IGF signalling to bone cells by IGFBP-3-specific proteolysis? Biochem Biophys Res Commun. 1991 Aug 30;179(1):579–585. [PubMed]
  • Ernst M, Rodan GA. Increased activity of insulin-like growth factor (IGF) in osteoblastic cells in the presence of growth hormone (GH): positive correlation with the presence of the GH-induced IGF-binding protein BP-3. Endocrinology. 1990 Aug;127(2):807–814. [PubMed]
  • Conover CA. Potentiation of insulin-like growth factor (IGF) action by IGF-binding protein-3: studies of underlying mechanism. Endocrinology. 1992 Jun;130(6):3191–3199. [PubMed]
  • Jones JI, Gockerman A, Busby WH, Jr, Camacho-Hubner C, Clemmons DR. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol. 1993 May;121(3):679–687. [PMC free article] [PubMed]
  • Ebeling PR, Jones JD, O'Fallon WM, Janes CH, Riggs BL. Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. J Clin Endocrinol Metab. 1993 Nov;77(5):1384–1387. [PubMed]
  • Ghiron LJ, Thompson JL, Holloway L, Hintz RL, Butterfield GE, Hoffman AR, Marcus R. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. J Bone Miner Res. 1995 Dec;10(12):1844–1852. [PubMed]
  • Bagi CM, Brommage R, Deleon L, Adams S, Rosen D, Sommer A. Benefit of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 on cancellous bone in ovariectomized rats. J Bone Miner Res. 1994 Aug;9(8):1301–1312. [PubMed]
  • Narusawa K, Nakamura T, Suzuki K, Matsuoka Y, Lee LJ, Tanaka H, Seino Y. The effects of recombinant human insulin-like growth factor (rhIGF)-1 and rhIGF-1/IGF binding protein-3 administration on rat osteopenia induced by ovariectomy with concomitant bilateral sciatic neurectomy. J Bone Miner Res. 1995 Dec;10(12):1853–1864. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...