Levels of Expression for BMP-7 and Several BMP Antagonists May Play an Integral Role in a Fracture Nonunion: A Pilot Study

  • Marc Fajardo
  • Chuan-Ju Liu
  • Kenneth Egol
Symposium: Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors


Delays in bone healing or even the development of a nonunion could be related to the concentrations and/or functions of the bone morphogenetic proteins (BMPs). The RNA expression profile of the BMPs within fracture nonunion tissue is unknown. This preliminary descriptive study was performed to define the RNA profiles of the BMPs, their receptors, and their inhibitors within human fracture nonunion tissue and correlate them to matched healing bone. All patients had hypertrophic nonunions. Tissue samples taken from the nonunion site of 15 patients undergoing surgical treatment for an established nonunion were analyzed. The RNA expression patterns of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8; BMP receptor Types IA, IB, and II; and the BMP inhibitors chordin, Noggin, Drm (Gremlin), and follistatin were determined in the nonunion (fibrous tissue) and healing bone (callus tissue) using quantitative real-time PCR. Comparison between the nonunion and healing bone samples revealed substantially elevated concentrations of BMP-4, Drm/Gremlin, follistatin, and Noggin in nonunion tissue when compared to healing bone. In contrast, BMP-7 concentration was higher in the healing bone. Our data suggest inhibition of BMP-7, by Drm (Gremlin), follistatin, and Noggin and upregulation of BMP-4 may play an integral role in the development of nonunions.


Healing Bone Fracture Callus Fracture Nonunions Nonunion Site Atrophic Nonunions 
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.



We thank Kiril Ilalov, Li Kong, and Michael Walsh for their help in this research endeavor.


  1. 1.
    Abe E. Function of BMPs and BMP antagonists in adult bone. Ann N Y Acad Sci. 2006;1068:41–53.CrossRefPubMedGoogle Scholar
  2. 2.
    Abe E, Yamamoto M, Taguchi Y, Lecka-Czernik B, O’Brien CA, Economides AN, Stahl N, Jilka RL, Manolagas, SC. Essential requirement of BMPs-2/4 for both osteoblast and osteoclast formation in murine bone marrow cultures from adult mice: antagonism by noggin. J Bone Miner Res. 2000;15:663–673.CrossRefPubMedGoogle Scholar
  3. 3.
    Behesti H, Holt JK, Sowden JC. The level of BMP4 signaling is critical for the regulation of distinct T-box gene expression domains and growth along the dorso-ventral axis of the optic cup. BMC Dev Biol. 2006;6:62.CrossRefPubMedGoogle Scholar
  4. 4.
    Brownlow HC, Reed A, Simpson AH. Growth factor expression during the development of atrophic non-union. Injury. 2001;32:519–524.CrossRefPubMedGoogle Scholar
  5. 5.
    Cheng H. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am. 2003;85:1544–1552.PubMedGoogle Scholar
  6. 6.
    Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83 Suppl 1(Pt 2):S151–S158.PubMedGoogle Scholar
  7. 7.
    Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19:71–88.CrossRefPubMedGoogle Scholar
  8. 8.
    Hendy GN, Kaji H, Sowa H, Lebrun JJ, Canaff L. Menin and TGF-beta superfamily member signaling via the Smad pathway in pituitary, parathyroid and osteoblast. Horm Metab Res. 2005;37:375–379.CrossRefPubMedGoogle Scholar
  9. 9.
    Kaplan FS, Fiori J, LS DLP, Ahn, J, Billings PC, Shore EM. Dysregulation of the BMP-4 signaling pathway in fibrodysplasia ossificans progressiva. Ann N Y Acad Sci. 2006;1068:54–65.CrossRefPubMedGoogle Scholar
  10. 10.
    Kloen P, Di Paola M, Borens O, Richmond J, Perino G, Helfet DL, Goumans MJ. BMP signaling components are expressed in human fracture callus. Bone. 2003;33:362–371.CrossRefPubMedGoogle Scholar
  11. 11.
    Kloen P, Doty SB, Gordon E, Rubel IF, Goumans MJ, Helfet DL. Expression and activation of the BMP-signaling components in human fracture nonunions. J Bone Joint Surg Am. 2002;84:1909–1918.CrossRefPubMedGoogle Scholar
  12. 12.
    Kochanowska I, Chaberek S, Wojtowiczi A, Marczynski B, Wlodarski K, Dytko M, Ostrowski K. Expression of genes for bone morphogenetic proteins BMP-2, BMP-4 and BMP-6 in various parts of the human skeleton. BMC Musculoskelet Disord. 2007;8:128.CrossRefPubMedGoogle Scholar
  13. 13.
    Kwong FN, Hoyland JA, Freemont AJ, Evans CH. Altered relative expression of BMPs and BMP inhibitors in cartilaginous areas of human fractures progressing towards nonunion. J Orthop Res. 2009;27:752–757.CrossRefPubMedGoogle Scholar
  14. 14.
    Leboy PS. Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci. 2006;1068:14–18.CrossRefPubMedGoogle Scholar
  15. 15.
    Niikura T, Hak DJ, Reddi AH. Global gene profiling reveals a downregulation of BMP gene expression in experimental atrophic nonunions compared to standard healing fractures. J Orthop Res. 2006;24:1463–1471.CrossRefPubMedGoogle Scholar
  16. 16.
    Onishi T, Ishidou Y, Nagamine T, Yone K, Imamura,T, Kato M, Sampath TK, Sakou T. Distinct and overlapping patterns of localization of bone morphogenetic protein (BMP) family members and a BMP type II receptor during fracture healing in rats. Bone. 1998;22:605–612.CrossRefPubMedGoogle Scholar
  17. 17.
    Rosen V. BMP and BMP inhibitors in bone. Ann N Y Acad Sci. 2006;1068:19–25.CrossRefPubMedGoogle Scholar
  18. 18.
    Tsialogiannis E, Polyzois I, Oak Tang Q, Pavlou G, Tsiridis E, Heliotis M, Tsiridis E. Targeting bone morphogenetic protein antagonists: in vitro and in vivo evidence of their role in bone metabolism. Expert Opin Ther Targets. 2009;13:123–137.CrossRefPubMedGoogle Scholar
  19. 19.
    Tsuji K, Cox K, Bandyopadhyay A, Harfe BD, Tabin CJ, Rosen V. BMP4 is dispensable for skeletogenesis and fracture-healing in the limb. J Bone Joint Surg Am. 2008;90 Suppl 1:14–18.CrossRefPubMedGoogle Scholar
  20. 20.
    Urist MR. A morphogenetic matrix for differentiation of bone tissue. Calcif Tissue Res. 1970;Suppl:98–101.Google Scholar
  21. 21.
    Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res. 1971;50:1392–1406.PubMedGoogle Scholar
  22. 22.
    Winkler D, Yu C, Geoghegan JC, Ojala EW, Skonier KE, Shpektor D, Sutherland MK, Latham JA. Noggin and sclerostin bone morphogenetic protein antagonists form a mutually inhibitory complex. J Biol Chem. 2004;279:36293–36298.CrossRefPubMedGoogle Scholar
  23. 23.
    Wordinger RJ, Agarwal R, Talati M, Fuller J, Lambert W, Clark AF. Expression of bone morphogenetic proteins (BMP), BMP receptors, and BMP associated proteins in human trabecular meshwork and optic nerve head cells and tissues. Mol Vis. 2002;8:241–250.PubMedGoogle Scholar
  24. 24.
    Wu X, Shi W, Cao X. Multiplicity of BMP signaling in skeletal development. Ann N Y Acad Sci. 2007;1116:29–49.CrossRefPubMedGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2009

Authors and Affiliations

  1. 1.Musculoskeletal Research Institute and The Bone Healing CenterNYU Hospital for Joint DiseasesNew YorkUSA

Personalised recommendations