Abstract
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.
Similar content being viewed by others
References
Abe E. Function of BMPs and BMP antagonists in adult bone. Ann N Y Acad Sci. 2006;1068:41–53.
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.
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.
Brownlow HC, Reed A, Simpson AH. Growth factor expression during the development of atrophic non-union. Injury. 2001;32:519–524.
Cheng H. Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs). J Bone Joint Surg Am. 2003;85:1544–1552.
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.
Guo X, Wang XF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19:71–88.
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.
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.
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.
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.
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.
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.
Leboy PS. Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci. 2006;1068:14–18.
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.
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.
Rosen V. BMP and BMP inhibitors in bone. Ann N Y Acad Sci. 2006;1068:19–25.
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.
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.
Urist MR. A morphogenetic matrix for differentiation of bone tissue. Calcif Tissue Res. 1970;Suppl:98–101.
Urist MR, Strates BS. Bone morphogenetic protein. J Dent Res. 1971;50:1392–1406.
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.
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.
Wu X, Shi W, Cao X. Multiplicity of BMP signaling in skeletal development. Ann N Y Acad Sci. 2007;1116:29–49.
Acknowledgments
We thank Kiril Ilalov, Li Kong, and Michael Walsh for their help in this research endeavor.
Author information
Authors and Affiliations
Corresponding author
Additional information
One of the authors (KE) has received research support from Synthes, Inc, West Chester, PA; Stryker Orthopaedics, Mahway, NJ; and Biomet Inc, Warsaw, IN; and is a consultant for Exactech, Inc, Gainesville, FL.
Each author certifies that his or her institution has approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained.
About this article
Cite this article
Fajardo, M., Liu, CJ. & Egol, K. Levels of Expression for BMP-7 and Several BMP Antagonists May Play an Integral Role in a Fracture Nonunion: A Pilot Study. Clin Orthop Relat Res 467, 3071–3078 (2009). https://doi.org/10.1007/s11999-009-0981-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11999-009-0981-9