• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Dec 15, 1992; 89(24): 11740–11744.
PMCID: PMC50632

Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression.

Abstract

Subcutaneous implantation of demineralized bone matrix initiates a sequence of developmental events, which culminate in endochondral bone formation. During early stages of development of matrix-induced implants, ED1, Ia-positive monocytes-macrophages were observed, suggesting that in the initial phases of the endochondral bone formation cascade, the bone-inductive protein osteogenin and related bone morphogenetic proteins (BMPs) might serve as potent chemoattractants to recruit circulating monocytes. In this investigation, we demonstrate that at concentrations of 10-100 fg/ml (0.3-3 fM), native bovine osteogenin and recombinant human BMP-2B (rhBMP-2B) induce the directed migration of human blood monocytes in vitro. This chemotactic response was associated with expression of BMP binding sites (receptors) on monocytes. About 750 receptors per cell were detected with an apparent dissociation constant of 200 pM. Both osteogenin and rhBMP-2B at higher concentrations (0.1-30 ng/ml) stimulated mRNA expression for an additional regulatory molecule, type beta 1 transforming growth factor (TGF-beta 1) in human monocytes. TGF-beta 1, in turn, is known to induce a cascade of events leading to matrix generation. Monocytes stimulated by TGF-beta are known to secrete a number of chemotactic and mitogenic cytokines that recruit endothelial and mesenchymal cells and promote their synthesis of collagen and associated matrix constituents. TGF-beta 1 in concert with these other cytokines and matrix components regulates chemotaxis, mesenchymal proliferation, differentiation, angiogenesis, and controlled synthesis of extracellular matrix. Our results demonstrate that osteogenin and related BMPs through their profound effects on monocyte recruitment and cytokine synthesis may promote additional successive steps in the endochondral bone formation cascade.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Urist MR. Bone: formation by autoinduction. Science. 1965 Nov 12;150(3698):893–899. [PubMed]
  • Reddi AH, Huggins C. Biochemical sequences in the transformation of normal fibroblasts in adolescent rats. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1601–1605. [PMC free article] [PubMed]
  • Reddi AH. Cell biology and biochemistry of endochondral bone development. Coll Relat Res. 1981 Feb;1(2):209–226. [PubMed]
  • Sampath TK, Reddi AH. Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7599–7603. [PMC free article] [PubMed]
  • Luyten FP, Cunningham NS, Ma S, Muthukumaran N, Hammonds RG, Nevins WB, Woods WI, Reddi AH. Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation. J Biol Chem. 1989 Aug 15;264(23):13377–13380. [PubMed]
  • Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. 1988 Dec 16;242(4885):1528–1534. [PubMed]
  • Wang EA, Rosen V, D'Alessandro JS, Bauduy M, Cordes P, Harada T, Israel DI, Hewick RM, Kerns KM, LaPan P, et al. Recombinant human bone morphogenetic protein induces bone formation. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2220–2224. [PMC free article] [PubMed]
  • Hammonds RG, Jr, Schwall R, Dudley A, Berkemeier L, Lai C, Lee J, Cunningham N, Reddi AH, Wood WI, Mason AJ. Bone-inducing activity of mature BMP-2b produced from a hybrid BMP-2a/2b precursor. Mol Endocrinol. 1991 Jan;5(1):149–155. [PubMed]
  • Ozkaynak E, Rueger DC, Drier EA, Corbett C, Ridge RJ, Sampath TK, Oppermann H. OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J. 1990 Jul;9(7):2085–2093. [PMC free article] [PubMed]
  • Heine U, Munoz EF, Flanders KC, Ellingsworth LR, Lam HY, Thompson NL, Roberts AB, Sporn MB. Role of transforming growth factor-beta in the development of the mouse embryo. J Cell Biol. 1987 Dec;105(6 Pt 2):2861–2876. [PMC free article] [PubMed]
  • Rosa F, Roberts AB, Danielpour D, Dart LL, Sporn MB, Dawid IB. Mesoderm induction in amphibians: the role of TGF-beta 2-like factors. Science. 1988 Feb 12;239(4841 Pt 1):783–785. [PubMed]
  • Seyedin SM, Thomas TC, Thompson AY, Rosen DM, Piez KA. Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2267–2271. [PMC free article] [PubMed]
  • Seyedin SM, Thompson AY, Bentz H, Rosen DM, McPherson JM, Conti A, Siegel NR, Galluppi GR, Piez KA. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986 May 5;261(13):5693–5695. [PubMed]
  • Seyedin SM, Segarini PR, Rosen DM, Thompson AY, Bentz H, Graycar J. Cartilage-inducing factor-B is a unique protein structurally and functionally related to transforming growth factor-beta. J Biol Chem. 1987 Feb 15;262(5):1946–1949. [PubMed]
  • Rosen DM, Stempien SA, Thompson AY, Seyedin SM. Transforming growth factor-beta modulates the expression of osteoblast and chondroblast phenotypes in vitro. J Cell Physiol. 1988 Mar;134(3):337–346. [PubMed]
  • Robey PG, Young MF, Flanders KC, Roche NS, Kondaiah P, Reddi AH, Termine JD, Sporn MB, Roberts AB. Osteoblasts synthesize and respond to transforming growth factor-type beta (TGF-beta) in vitro. J Cell Biol. 1987 Jul;105(1):457–463. [PMC free article] [PubMed]
  • Carrington JL, Roberts AB, Flanders KC, Roche NS, Reddi AH. Accumulation, localization, and compartmentation of transforming growth factor beta during endochondral bone development. J Cell Biol. 1988 Nov;107(5):1969–1975. [PMC free article] [PubMed]
  • Noda M, Camilliere JJ. In vivo stimulation of bone formation by transforming growth factor-beta. Endocrinology. 1989 Jun;124(6):2991–2994. [PubMed]
  • Joyce ME, Roberts AB, Sporn MB, Bolander ME. Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur. J Cell Biol. 1990 Jun;110(6):2195–2207. [PMC free article] [PubMed]
  • Allen JB, Malone DG, Wahl SM, Calandra GB, Wilder RL. Role of the thymus in streptococcal cell wall-induced arthritis and hepatic granuloma formation. Comparative studies of pathology and cell wall distribution in athymic and euthymic rats. J Clin Invest. 1985 Sep;76(3):1042–1056. [PMC free article] [PubMed]
  • Wahl LM, Katona IM, Wilder RL, Winter CC, Haraoui B, Scher I, Wahl SM. Isolation of human mononuclear cell subsets by counterflow centrifugal elutriation (CCE). I. Characterization of B-lymphocyte-, T-lymphocyte-, and monocyte-enriched fractions by flow cytometric analysis. Cell Immunol. 1984 May;85(2):373–383. [PubMed]
  • Ohura K, Katona IM, Wahl LM, Chenoweth DE, Wahl SM. Co-expression of chemotactic ligand receptors on human peripheral blood monocytes. J Immunol. 1987 Apr 15;138(8):2633–2639. [PubMed]
  • Frolik CA, Wakefield LM, Smith DM, Sporn MB. Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts. J Biol Chem. 1984 Sep 10;259(17):10995–11000. [PubMed]
  • Paralkar VM, Hammonds RG, Reddi AH. Identification and characterization of cellular binding proteins (receptors) for recombinant human bone morphogenetic protein 2B, an initiator of bone differentiation cascade. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3397–3401. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. [PubMed]
  • March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, Gillis S, Henney CS, Kronheim SR, Grabstein K, et al. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985 Jun 20;315(6021):641–647. [PubMed]
  • Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149–154. [PubMed]
  • Piechaczyk M, Blanchard JM, Marty L, Dani C, Panabieres F, El Sabouty S, Fort P, Jeanteur P. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucleic Acids Res. 1984 Sep 25;12(18):6951–6963. [PMC free article] [PubMed]
  • Zigmond SH, Hirsch JG. Leukocyte locomotion and chemotaxis. New methods for evaluation, and demonstration of a cell-derived chemotactic factor. J Exp Med. 1973 Feb 1;137(2):387–410. [PMC free article] [PubMed]
  • Wahl SM, McCartney-Francis N, Allen JB, Dougherty EB, Dougherty SF. Macrophage production of TGF-beta and regulation by TGF-beta. Ann N Y Acad Sci. 1990;593:188–196. [PubMed]
  • Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, et al. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. [PMC free article] [PubMed]
  • Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. [PMC free article] [PubMed]
  • Henricson A, Hulth A, Johnell O. The occurrence of accessory immunologic cells in bone induction. Clin Orthop Relat Res. 1991 Mar;(264):270–277. [PubMed]
  • Snyderman R, Pike MC. Chemoattractant receptors on phagocytic cells. Annu Rev Immunol. 1984;2:257–281. [PubMed]
  • Wiseman DM, Polverini PJ, Kamp DW, Leibovich SJ. Transforming growth factor-beta (TGF beta) is chemotactic for human monocytes and induces their expression of angiogenic activity. Biochem Biophys Res Commun. 1988 Dec 15;157(2):793–800. [PubMed]
  • Sampath TK, Muthukumaran N, Reddi AH. Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7109–7113. [PMC free article] [PubMed]
  • McCartney-Francis N, Mizel D, Wong H, Wahl L, Wahl S. TGF-beta regulates production of growth factors and TGF-beta by human peripheral blood monocytes. Growth Factors. 1990;4(1):27–35. [PubMed]
  • Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987 Jan 1;165(1):251–256. [PMC free article] [PubMed]
  • Pfeilschifter J, Wolf O, Naumann A, Minne HW, Mundy GR, Ziegler R. Chemotactic response of osteoblastlike cells to transforming growth factor beta. J Bone Miner Res. 1990 Aug;5(8):825–830. [PubMed]
  • Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. [PubMed]
  • Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed]
  • Varga J, Rosenbloom J, Jimenez SA. Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J. 1987 Nov 1;247(3):597–604. [PMC free article] [PubMed]
  • Sporn MB, Roberts AB, Wakefield LM, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. [PMC free article] [PubMed]
  • Keski-Oja J, Blasi F, Leof EB, Moses HL. Regulation of the synthesis and activity of urokinase plasminogen activator in A549 human lung carcinoma cells by transforming growth factor-beta. J Cell Biol. 1988 Feb;106(2):451–459. [PMC free article] [PubMed]
  • Foidart JM, Reddi AH. Immunofluorescent localization of type IV collagen and laminin during endochondral bone differentiation and regulation by pituitary growth hormone. Dev Biol. 1980 Mar;75(1):130–136. [PubMed]
  • Paralkar VM, Nandedkar AK, Pointer RH, Kleinman HK, Reddi AH. Interaction of osteogenin, a heparin binding bone morphogenetic protein, with type IV collagen. J Biol Chem. 1990 Oct 5;265(28):17281–17284. [PubMed]
  • Paralkar VM, Vukicevic S, Reddi AH. Transforming growth factor beta type 1 binds to collagen IV of basement membrane matrix: implications for development. Dev Biol. 1991 Feb;143(2):303–308. [PubMed]
  • Vukicevic S, Luyten FP, Reddi AH. Stimulation of the expression of osteogenic and chondrogenic phenotypes in vitro by osteogenin. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8793–8797. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...