• 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 1, 1997; 99(9): 2284–2292.
PMCID: PMC508061

A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo.

Abstract

Osteoclastic bone degradation requires intimacy between the matrix and the resorptive cell. While the precise role the integrin alpha(v)beta3 plays in the process is not yet understood, occupancy of the heterodimer by soluble ligand or by blocking antibody effectively inhibits bone resorption in vitro and in vivo, suggesting that alpha(v)beta3 blockade may prevent postmenopausal osteoporosis. Thus, we identified a synthetic chemical peptide mimetic, beta-[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-+ ++oxoethyl]amino-3-pyridinepropanoic acid, bistrifluoroacetate (SC56631) based upon the alpha(v)beta3 ligand, Arg-Gly-Asp (RGD), which recognizes the isolated integrin, and its relative, alpha(v)beta5, as effectively as does the natural peptide. The mimetic dampens osteoclastic bone resorption in vitro and in vivo. Most importantly, intravenous administration of the mimetic prevents the 55% loss of trabecular bone sustained by rats within 6 wk of oophorectomy. Histological examination of bones taken from SC56631-treated, oophorectomized animals also demonstrates the compound's bone sparing properties and its capacity to decrease osteoclast number. Thus, an RGD mimetic prevents the rapid bone loss that accompanies estrogen withdrawal.

Full Text

The Full Text of this article is available as a PDF (381K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Wronski TJ, Cintrón M, Doherty AL, Dann LM. Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology. 1988 Aug;123(2):681–686. [PubMed]
  • Blair HC, Kahn AJ, Crouch EC, Jeffrey JJ, Teitelbaum SL. Isolated osteoclasts resorb the organic and inorganic components of bone. J Cell Biol. 1986 Apr;102(4):1164–1172. [PMC free article] [PubMed]
  • Alvarez JI, Teitelbaum SL, Blair HC, Greenfield EM, Athanasou NA, Ross FP. Generation of avian cells resembling osteoclasts from mononuclear phagocytes. Endocrinology. 1991 May;128(5):2324–2335. [PubMed]
  • Shioi A, Ross FP, Teitelbaum SL. Enrichment of generated murine osteoclasts. Calcif Tissue Int. 1994 Nov;55(5):387–394. [PubMed]
  • Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, Koga T, Martin TJ, Suda T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7260–7264. [PMC free article] [PubMed]
  • Fallon MD, Teitelbaum SL, Kahn AJ. Multinucleation enhances macrophage-mediated bone resorption. Lab Invest. 1983 Aug;49(2):159–164. [PubMed]
  • Blair HC, Teitelbaum SL, Ghiselli R, Gluck S. Osteoclastic bone resorption by a polarized vacuolar proton pump. Science. 1989 Aug 25;245(4920):855–857. [PubMed]
  • Blair HC, Teitelbaum SL, Grosso LE, Lacey DL, Tan HL, McCourt DW, Jeffrey JJ. Extracellular-matrix degradation at acid pH. Avian osteoclast acid collagenase isolation and characterization. Biochem J. 1993 Mar 15;290(Pt 3):873–884. [PMC free article] [PubMed]
  • Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 1988 Apr;175(2):266–276. [PubMed]
  • Miyauchi A, Alvarez J, Greenfield EM, Teti A, Grano M, Colucci S, Zambonin-Zallone A, Ross FP, Teitelbaum SL, Cheresh D, et al. Recognition of osteopontin and related peptides by an alpha v beta 3 integrin stimulates immediate cell signals in osteoclasts. J Biol Chem. 1991 Oct 25;266(30):20369–20374. [PubMed]
  • Crippes BA, Engleman VW, Settle SL, Delarco J, Ornberg RL, Helfrich MH, Horton MA, Nickols GA. Antibody to beta3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. Endocrinology. 1996 Mar;137(3):918–924. [PubMed]
  • Horton MA, Taylor ML, Arnett TR, Helfrich MH. Arg-Gly-Asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. Exp Cell Res. 1991 Aug;195(2):368–375. [PubMed]
  • Ross FP, Chappel J, Alvarez JI, Sander D, Butler WT, Farach-Carson MC, Mintz KA, Robey PG, Teitelbaum SL, Cheresh DA. Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem. 1993 May 5;268(13):9901–9907. [PubMed]
  • Mimura H, Cao X, Ross FP, Chiba M, Teitelbaum SL. 1,25-Dihydroxyvitamin D3 transcriptionally activates the beta 3-integrin subunit gene in avian osteoclast precursors. Endocrinology. 1994 Mar;134(3):1061–1066. [PubMed]
  • Cao X, Ross FP, Zhang L, MacDonald PN, Chappel J, Teitelbaum SL. Cloning of the promoter for the avian integrin beta 3 subunit gene and its regulation by 1,25-dihydroxyvitamin D3. J Biol Chem. 1993 Dec 25;268(36):27371–27380. [PubMed]
  • Fisher JE, Caulfield MP, Sato M, Quartuccio HA, Gould RJ, Garsky VM, Rodan GA, Rosenblatt M. Inhibition of osteoclastic bone resorption in vivo by echistatin, an "arginyl-glycyl-aspartyl" (RGD)-containing protein. Endocrinology. 1993 Mar;132(3):1411–1413. [PubMed]
  • Yatohgo T, Izumi M, Kashiwagi H, Hayashi M. Novel purification of vitronectin from human plasma by heparin affinity chromatography. Cell Struct Funct. 1988 Aug;13(4):281–292. [PubMed]
  • Charo IF, Nannizzi L, Phillips DR, Hsu MA, Scarborough RM. Inhibition of fibrinogen binding to GP IIb-IIIa by a GP IIIa peptide. J Biol Chem. 1991 Jan 25;266(3):1415–1421. [PubMed]
  • Pytela R, Pierschbacher MD, Argraves S, Suzuki S, Ruoslahti E. Arginine-glycine-aspartic acid adhesion receptors. Methods Enzymol. 1987;144:475–489. [PubMed]
  • Niiya K, Hodson E, Bader R, Byers-Ward V, Koziol JA, Plow EF, Ruggeri ZM. Increased surface expression of the membrane glycoprotein IIb/IIIa complex induced by platelet activation. Relationship to the binding of fibrinogen and platelet aggregation. Blood. 1987 Aug;70(2):475–483. [PubMed]
  • Lampugnani MG, Bernasconi S, Neri P, Lozzi L, Gavazzi I, Marchisio PC, Dejana E. Role of manganese in MG-63 osteosarcoma cell attachment to fibrinogen and von Willebrand factor. Lab Invest. 1991 Jul;65(1):96–103. [PubMed]
  • Blystone SD, Graham IL, Lindberg FP, Brown EJ. Integrin alpha v beta 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor alpha 5 beta 1. J Cell Biol. 1994 Nov;127(4):1129–1137. [PMC free article] [PubMed]
  • Mould AP, Akiyama SK, Humphries MJ. Regulation of integrin alpha 5 beta 1-fibronectin interactions by divalent cations. Evidence for distinct classes of binding sites for Mn2+, Mg2+, and Ca2+. J Biol Chem. 1995 Nov 3;270(44):26270–26277. [PubMed]
  • Bodary SC, McLean JW. The integrin beta 1 subunit associates with the vitronectin receptor alpha v subunit to form a novel vitronectin receptor in a human embryonic kidney cell line. J Biol Chem. 1990 Apr 15;265(11):5938–5941. [PubMed]
  • Hu DD, Lin EC, Kovach NL, Hoyer JR, Smith JW. A biochemical characterization of the binding of osteopontin to integrins alpha v beta 1 and alpha v beta 5. J Biol Chem. 1995 Nov 3;270(44):26232–26238. [PubMed]
  • Fenton AJ, Martin TJ, Nicholson GC. Long-term culture of disaggregated rat osteoclasts: inhibition of bone resorption and reduction of osteoclast-like cell number by calcitonin and PTHrP[107-139]. J Cell Physiol. 1993 Apr;155(1):1–7. [PubMed]
  • Zucker MB. Platelet aggregation measured by the photometric method. Methods Enzymol. 1989;169:117–133. [PubMed]
  • Harris RA, Carnes DL, Forte LR. Reduction of brain calcium after consumption of diets deficient in calcium or vitamin D. J Neurochem. 1981 Feb;36(2):460–466. [PubMed]
  • Nesbitt S, Nesbit A, Helfrich M, Horton M. Biochemical characterization of human osteoclast integrins. Osteoclasts express alpha v beta 3, alpha 2 beta 1, and alpha v beta 1 integrins. J Biol Chem. 1993 Aug 5;268(22):16737–16745. [PubMed]
  • Holtrop ME, Raisz LG. Comparison of the effects of 1,25-dihydroxycholecalciferol, prostaglandin E2, and osteoclast-activating factor with parathyroid hormone on the ultrastructure of osteoclasts in cultured long bones of fetal rats. Calcif Tissue Int. 1979;29(3):201–205. [PubMed]
  • Vänänen HK, Horton M. The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure. J Cell Sci. 1995 Aug;108(Pt 8):2729–2732. [PubMed]
  • Holtrop ME, Cox KA, Clark MB, Holick MF, Anast CS. 1,25-dihydroxycholecalciferol stimulates osteoclasts in rat bones in the absence of parathyroid hormone. Endocrinology. 1981 Jun;108(6):2293–2301. [PubMed]
  • Reinholt FP, Hultenby K, Oldberg A, Heinegård D. Osteopontin--a possible anchor of osteoclasts to bone. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4473–4475. [PMC free article] [PubMed]
  • Lakkakorpi PT, Horton MA, Helfrich MH, Karhukorpi EK, Vänänen HK. Vitronectin receptor has a role in bone resorption but does not mediate tight sealing zone attachment of osteoclasts to the bone surface. J Cell Biol. 1991 Nov;115(4):1179–1186. [PMC free article] [PubMed]
  • Sato M, Sardana MK, Grasser WA, Garsky VM, Murray JM, Gould RJ. Echistatin is a potent inhibitor of bone resorption in culture. J Cell Biol. 1990 Oct;111(4):1713–1723. [PMC free article] [PubMed]
  • Riggs BL, Melton LJ., 3rd Evidence for two distinct syndromes of involutional osteoporosis. Am J Med. 1983 Dec;75(6):899–901. [PubMed]
  • Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992 Jul 3;257(5066):88–91. [PubMed]
  • Fitzgerald LA, Steiner B, Rall SC, Jr, Lo SS, Phillips DR. Protein sequence of endothelial glycoprotein IIIa derived from a cDNA clone. Identity with platelet glycoprotein IIIa and similarity to "integrin". J Biol Chem. 1987 Mar 25;262(9):3936–3939. [PubMed]
  • Nicholson NS, Panzer-Knodle SG, King LW, Taite BB, Keller BT, Tjoeng FS, Engleman VW, Giorgio TD, Feigen LP. SC-49992--a potent and specific inhibitor of platelet aggregation. Thromb Res. 1994 Jun 1;74(5):523–535. [PubMed]
  • Helfrich MH, Nesbitt SA, Lakkakorpi PT, Barnes MJ, Bodary SC, Shankar G, Mason WT, Mendrick DL, Vänänen HK, Horton MA. Beta 1 integrins and osteoclast function: involvement in collagen recognition and bone resorption. Bone. 1996 Oct;19(4):317–328. [PubMed]
  • van der Pluijm G, Mouthaan H, Baas C, de Groot H, Papapoulos S, Löwik C. Integrins and osteoclastic resorption in three bone organ cultures: differential sensitivity to synthetic Arg-Gly-Asp peptides during osteoclast formation. J Bone Miner Res. 1994 Jul;9(7):1021–1028. [PubMed]
  • Hiura K, Lim SS, Little SP, Lin S, Sato M. Differentiation dependent expression of tensin and cortactin in chicken osteoclasts. Cell Motil Cytoskeleton. 1995;30(4):272–284. [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

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    Compound
    PubChem Compound 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...