Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1998 May 15; 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.


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


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


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

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...