Characterization of the IGF Regulatory System in Bone

  • Subburaman Mohan
  • David J. Baylink
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 343)


There are two major dynamic processes in bone: bone formation and bone resorption which determine the volume of bone and ultimately its strength. Because bone is a tissue which is continuously remodeling, bone formation is an essential part of skeletal maintenance even after the growth period where bone formation is obviously essential. Moreover, bone has a remarkable regenerative potential which enables it to remodel itself in response to changing physical demands, and to repair itself after injury. In the majority of the adult skeleton, bone formation is confined to specific remodeling sites. Whether bone is lost or gained will depend on the extent of bone formation in each one of these sites. With regard to the mediators of bone formation, growth factors have received much attention. Of the several growth factors present in bone (IGF-I, IGF-II, TGF-β1, TGF-β2, PDGF, basic FGF, acidic FGF and BMPs), there is now sufficient evidence to document an important role for the IGFs in the local regulation of bone formation. In this paper we describe the components of the IGF regulatory system and discuss evidence supporting a role for IGFs in the local regulation of bone formation.


Bone Formation Bone Cell Human Bone Cell Bone Cell Proliferation Colon Cancer Cell Growth Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    S. Mohan, DJ. Baylink. Bone growth factors. Clin Orthoped Rel Res 263:30(1991).Google Scholar
  2. 2.
    S. Mohan, DJ. Baylink. The role of insulin-like growth factor-II in the coupling of bone formation to resorption. in: “Modern Concepts of Insulin-Like Growth Factors,“ E.M. Spencer, ed., Elsevier, New York (1991).Google Scholar
  3. 3.
    J. Zapf, E.R. Froesch. Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role. Horm Res 24:121 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    A.G. Johansson, E. Lindh, S. Ljunghall. Insulin-like growth factor I stimulates bone turnover in osteoporosis. Lancet 339:1619 (1992).PubMedCrossRefGoogle Scholar
  5. 5.
    S. Mohan, C.M. Bautista, J.E. Wergedal, D.J. Baylink. Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: A potential local regulator of IGF action. Proc NatlAcadSci USA 86:8338 (1989).CrossRefGoogle Scholar
  6. 6.
    S. Mohan, J. Dequeker, R. Van den Eyned, J. Peeters, J. Aerssens, DJ. Baylink. Increased insulin-like growth factor (IGF)-I and IGF-II in bone from patients with osteoarthritis. J Bone and Mine Res 6:S131 (1991).Google Scholar
  7. 7.
    V. Nicolas, A. Prewett, P. Bettica, Evidence for a progressive decline of IGF-I in human bone in both males and females as a function of age. J Bone Min Res 7:S255 (1992).Google Scholar
  8. 8.
    S. Mohan. Insulin-like growth factor binding proteins in bone cell regulation. Growth Regulation 3:65 (1993).Google Scholar
  9. 9.
    R.M. Maciel, A.C. Moses, G. Villone, D. Tramontano, S.H. Ingbar. Demonstration of the production and physiological role of insulin-like growth factor II in rat thyroid follicular cells in culture. J Clin Invest 82:1846 (1988).CrossRefGoogle Scholar
  10. 10.
    A. Gray, A.W. Tam, T.J. Dull, J. Hayflick, J. Pintar, W.K. Cavenee, A. Koufos, A. Ullrich. Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA 6:283 (1987).PubMedCrossRefGoogle Scholar
  11. 11.
    T.L. McCarthy, M. Centrella, E. Canalis. Parathyroid hormone enhances the transcript and polypeptide levels of insulin-like growth factor I in osteoblast-enriched cultures from fetal rat bone. Endocrinology 124:1247 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    R.D. Finkelman S. Mohan, T.A. Linkhart, S.M. Abraham, J.P. Boussy, DJ. Baylink. PTH stimulates the proliferation of TE-85 human osteosarcoma cells by a mechanism not involving either increased cAMP or increased secretion of IGF-I, IGF-II or TGF beta. Bone Mineral 16:89 (1992).CrossRefGoogle Scholar
  13. 13.
    S.H. Scharia, D.D. Strong, S. Mohan, D.J. Baylink, T.A. Linkhart. 1,25 dihydroxyvitamin D3 differentially regulates the production of IGF-I and IGFBP-4 in mouse osteoblasts. Endocrinology 129:3139 (1991).CrossRefGoogle Scholar
  14. 14.
    R.J. Fitzsimmons, D.D. Strong, S. Mohan, D.J. Baylink. Low-amplitude, low-frequency electric field-stimulated bone cell proliferation may in part be mediated by increase IGF-II release. J Cell Physiol 150:84,1992.PubMedCrossRefGoogle Scholar
  15. 15.
    F.T. Tremollieres, D.D. Strong, D.J.Baylink, S. Mohan. Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-II production. Acta Endocrinol (Copenh) 126:329 (1992).Google Scholar
  16. 16.
    R. Knutsen, K. Sampath, D.J. Baylink, S. Mohan. Evidence that osteogenic protein-1 (OP-1) may modulate its effects on human bone cell proliferation (HBC) by regulating the local production of insulin-like growth factors. J Bone and Min Res 7:S104 (1992).Google Scholar
  17. 17.
    S. Shimasaki, N. Ling. Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). Prog in Growth Factor Res 1:243 (1991).CrossRefGoogle Scholar
  18. 18.
    S. Mohan, D.J. Baylink. Isolation and characterization of insulin-like growth factor binding proteins produced by human bone cells in vitro. JBone Min Res 6:S141 (1991).Google Scholar
  19. 19.
    C.M. Bautista, D.J. Baylink, S. Mohan. Isolation of a novel insulin-like growth factor (IGF) binding protein from human bone: A potential candidate for fixing IGF-II in human bone. Biochem Biophys Res Commun 176:756 (1991).PubMedCrossRefGoogle Scholar
  20. 20.
    C. Conover. Potentiation of insulin-like growth factor (IGF) action by IGF binding protein-3: Studies of underlying mechanism. Endocrinology 130:3191 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    M. Rashmi, D.D. Strong, D.J. Baylink, S. Mohan. Stimulation of human bone cell proliferation by an antisense oligodeoxyribonucleotide to IGFBP-4 mRNA. J Bone Min Res 7:S124 (1992).Google Scholar
  22. 22.
    P.T. Cheung, E.P. Smith, S. Shimasaki, N. Ling, S.D. Chernausek. Characterization of an insulin-like growth factor binding protein (IGFBP-4) produced by B104 rat neuronal cell line: Chemical and biological properties and differential synthesis by sublines. Endocrinology 129:1006 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    J.M. Culouscou, M. Shoyab. Purification of a colon cancer cell growth inhibitor and its identification as an insulin-like growth factor binding protein. Cancer Res 51:2813 (1991).PubMedGoogle Scholar
  24. 24.
    D.L. Andress, R.S. Birnbaum. A novel insulin-like growth factor binding protein secreted by osteoblast-like cells. Biochem Biophys Res Commun 176:213 (1991).PubMedCrossRefGoogle Scholar
  25. 25.
    D. LaTour, S. Mohan, T.A. Linkhart, D.J. Baylink, D.D. Strong. Inhibitory insulin-like growth factor binding protein: Cloning, complete sequence and physiological regulation. Molec Endocrinol 4:1806 (1990).CrossRefGoogle Scholar
  26. 26.
    O. Torring, A.F. Firek, H. Heath III, C.A. Conover. Parathyroid hormone and parathyroid hormone-related peptide stimulate insulin-like growth factor-binding protein secretion by rat osteoblast-like cells through a adenosine 3’,5’-monophosphate-dependent mechanism. Endocrinology 128:1006 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    C. Rosen, L.R. Donahue, S. Hunter, M. Holick, H. Kavookjian, A. Kirschenbaum, S. Mohan, D.J. Baylink. The 24/25 kDa serum insulinlike growth factor-binding protein is increased in elderly women with hip and spine fractures. J Clin Endocinol Metab 74:24 (1992).CrossRefGoogle Scholar
  28. 28.
    K. Lee, S. Mohan, D.J. Baylink, D.D. Strong. Evidence that transcriptional regulation of insulin-like growth factor binding protein-4 (IGFBP-4) gene in human bone cells. JBone Min Res 7:S232 (1992).Google Scholar
  29. 29.
    S.H. Scharia, C. Rosen, D.D. Strong, S. Mohan, D.J. Baylink, T.A. Linkhart. Stimulatory effect of l,25(OH)2D3 on IGFBP-4 secretion in bone cells. 2nd International Workshop on IGFBPs ,Opio, France (1992).Google Scholar
  30. 30.
    U.G. Lempert, D.D. Strong, D.J. Baylink, S. Mohan. Effects of progesterone on the mRNA levels of IGFBP-3, IGFBP-4, IGFBP-5 and IGFBP-6 in human osteoblastic cells. 2nd International Workshop on IGFBPs ,Opio, France (1992).Google Scholar
  31. 31.
    S. Mohan, D.D. Strong, U.G. Lempert, J.E. Wergedal, D.J. Baylink. Studies on regulation of insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-4 production in human bone cells. Acta Endocinology 127:555 (1992).Google Scholar
  32. 32.
    U.G. Lempert, C. Bautista, D.D. Strong, D.J. Baylink, S. Mohan. Purification of a novel human bone derived inulin-like growth factor binding protein (hBD-IGFBP): A potential candidate for fixing IGF-II in bone. J Bone Min Res 6:S250 (1991).Google Scholar
  33. 33.
    L.C. Guidice, E.M. Farrel, H. Pham, G. Lamson, R.G. Rosenfeld. Insulin-like growth factor bidning proteins in maternal serum throughout gestation and in the puerperium: Effects of a pregnancy-associated serum protease activity. JClin Endocrinol Metab 71:806 (1990).CrossRefGoogle Scholar
  34. 34.
    P. Hossenlopp, B. Segovia, C. Lassarre, M. Roghani, M.Bredon, M. Binoux. Evidence of enzymzatic degradation of insulin-like growth factor binding proteins in the 150K complex during pregnancy. J Clin Endocrinol Metab 71:797 (1990).PubMedCrossRefGoogle Scholar
  35. 35.
    S. Kanzaki, Malpe R. Baylink D.J., S. Mohan. Evidence that human bone cells (HBC) in culture produce insulin-like growth factor binding protein (IGFBP)-4 and -5 proteases. 75th Annual Meeting, The Endocrine Society In Press (1993).Google Scholar
  36. 36.
    P.G. Campbell, J.F. Novak, T.B. Yanosick, J.H. McMaster. Involvement of the plasmin system in dissociation of the insulin-like growth factor binding protein complex. Endocrinology 130:1401 (1992).PubMedCrossRefGoogle Scholar
  37. 37.
    J.R. Farley, N. Tarbaux, L.A. Murphy, T. Masuda, D.J. Baylink. In vitro evidence that bone formation may be coupled to bone resorptioon by release of mitogen(s) from resorbing bone. Metabolism 36:314 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Subburaman Mohan
    • 1
  • David J. Baylink
    • 1
  1. 1.Departments of Medicine, Biochemistry and PhysiologyLoma Linda University and Pettis VA Medical CenterLoma LindaUSA

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