BMP Signaling in Regenerative Medicine

BMP Signaling in Regenerative Medicine

Julia Zimmer (Charité-Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies, Germany), Elisa Degenkolbe (Charité-Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies, Germany), Britt Wildemann (Charité-Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies, Germany) and Petra Seemann (Charité-Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies, Germany)
DOI: 10.4018/978-1-4666-2506-8.ch001
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More than 40 years after the discovery of Bone Morphogenetic Proteins (BMPs) as bone inducers, a whole protein family of growth factors connected to a wide variety of functions in embryonic development, homeostasis, and regeneration has been characterized. Today, BMP2 and BMP7 are already used in the clinic to promote vertebral fusions and restoration of non-union fractures. Besides describing present clinical applications, the authors review ongoing trials highlighting the future possibilities of BMPs in medicine. Apparently, the physiological roles of BMPs have expanded their range from bone growth induction and connective tissue regeneration to cancer diagnosis/treatment and cardiovascular disease prevention.
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The matrix bone has fascinated scientists throughout centuries beginning with Hippocrates who initially theorized the capacity of endogenous substances for medicinal purposes. Even though earlier studies in the field of bone regeneration are known, Dr. Marshall Raymond Urist, an orthopedic surgeon, made the landmark discovery in 1965. Urist described his elusive observation with the following words: “Wandering histiocytes, foreign body giant cells, and inflammatory connective-tissue cells are stimulated by degradation products of dead matrix to grow in and repopulate the area of an implant of decalcified bone” (Urist, 1965). From this discovery, that new bone is formed upon applying a demineralized bone extract in a rabbit muscle he concluded that a certain agent within this crude protein mix has to be responsible for such an ectopic bone growth. He named this substance Bone Morphogenetic Protein, generally known as BMP.

Over the past five decades, cloning and purification of BMPs as well as the mechanisms of BMP signal transduction have been extensively studied and reviewed (Chen, Zhao, & Mundy, 2004; Wang, et al., 1990; Wozney, et al., 1988). To date, BMPs are well characterized and known as multi-functional growth factors belonging to the transforming growth factor ß (TGFß) superfamily. The superfamily of TGFß ligands is a phylogenetically conserved group of signaling molecules that comprises over 30 members in mammals including TGFβs, Activins, Inhibins, Bone Morphogenetic Proteins (BMPs), Growth and Differentiation Factors (GDFs), Myostatin, Leftys, and Müllerian-Inhibiting Substance (MIS) (Figure 1) (Wu & Hill, 2009).

Figure 1.

Phylogenetic tree of the human TGF-ß superfamily. Phylogenetic tree derived from protein alignments of preproproteins of the members of the TGF-ß superfamily.

In this chapter, we will start by introducing BMPs in a general manner covering synthesis, structure, signaling, and regulation. The complexity of these systems already hints towards the importance of BMPs in human diseases, which will be the focus of the following paragraph. By understanding BMPs and also the associated diseases many researchers try to turn the table and utilize BMPs as drugs. We will present current efforts to find BMP treatments for a wide variety of diseases like kidney or liver failure. However, the original field for BMP application is the skeleton and until now only two members of the BMP family are approved for clinical application in bone regeneration, namely BMP2 and BMP7. Their development and role in today’s clinical practice, especially in the field of bone regeneration, will be a main focus of this chapter. Finally, we will discuss the current problems of BMP therapy and present possible solutions.



BMP Synthesis

BMPs are synthesized as large precursor proteins consisting of an N-terminal signal peptide, a pro-domain, and a mature peptide (Eder & Fersht, 1995; Kuhfahl, et al., 2011; Xiao, Xiang, & Shao, 2007). Following N-terminal proteolysis of the signal peptide, the pro- and mature domain remain non-covalently associated and undergo dimerization whereby two monomers are assembled in an antiparallel manner. Prior to receptor binding, the active BMP dimer is derived by intra- or extracellular cleavage within the prodomain at an Arg-X-X-Arg site by members of the Subtilisin-like Proprotein Convertase (SPC) family (Constam & Robertson, 1999; Ploger, et al., 2008).

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Editorial Advisory Board
Table of Contents
James Adjaye
Andriani Daskalaki
Chapter 1
Julia Zimmer, Elisa Degenkolbe, Britt Wildemann, Petra Seemann
More than 40 years after the discovery of Bone Morphogenetic Proteins (BMPs) as bone inducers, a whole protein family of growth factors connected to... Sample PDF
BMP Signaling in Regenerative Medicine
Chapter 2
George I. Lambrou, Maria Adamaki, Apostolos Zaravinos
There is an increasing tendency to use stem cells as potential therapeutics in various human diseases. This is a rapidly progressing field, believed... Sample PDF
Proliferation and Regeneration: Methodologies in Cancer Treatment and Post-Treatment Tissue Reconstruction
Chapter 3
Svetoslav Nikolov, Mukhtar Ullah, Momchil Nenov, Julio Vera Gonzalez, Peter Raasch, Olaf Wolkenhauer
Mathematical modeling is increasingly used to improve our understanding of colorectal cancer. In the first part of this chapter, the authors give a... Sample PDF
Modeling Colorectal Cancer: A Stability Analysis Approach
Chapter 4
Ana M. Sotoca, Michael Weber, Everardus J. J. van Zoelen
Human mesenchymal stem cells have a high potential in regenerative medicine. They can be isolated from a variety of adult tissues, including bone... Sample PDF
Gene Expression Regulation underlying Osteo-, Adipo-, and Chondro-Genic Lineage Commitment of Human Mesenchymal Stem Cells
Chapter 5
Franz Ricklefs, Sonja Schrepfer
Current medical research is focused on two particular types of stem cells, adult stem cells and embryonic stem cells. Both cell types demonstrate a... Sample PDF
Immunogenicity of Stem Cells
Chapter 6
Sonja Schallenberg, Cathleen Petzold, Julia Riewaldt, Karsten Kretschmer
CD4+CD25+ regulatory T (Treg) cells expressing the forkhead box transcription factor Foxp3 have a vital function in the maintenance of immune... Sample PDF
Regulatory T Cell-Based Immunotherapy: Prospects of Antigen-Specific Tolerance Induction
Chapter 7
Ali Mobasheri
This chapter reviews the structure and function of articular cartilage and the pathogenesis of Osteoarthritis (OA) before exploring the challenges... Sample PDF
Regeneration of Articular Cartilage: Opportunities, Challenges, and Perspectives
Chapter 8
Frank Martin, Mario Lehmann, Ursula Anderer
Since our society is characterized by an increasing age of its people on the one hand and a high number of persons dealing with sports on the other... Sample PDF
Generation of Scaffold Free 3-D Cartilage-Like Microtissues from Human Chondrocytes
Chapter 9
The Hidden Markov Brains  (pages 195-214)
Tuan D. Pham
This chapter presents Hidden Markov models (HMM) of the brain on Magnetic Resonance Imaging (MRI) for the inference of white matter hyperintensities... Sample PDF
The Hidden Markov Brains
Chapter 10
Arghya Paul
The breakthrough technologies of stent have revolutionized the medical industry, particularly in the field of percutaneous coronary interventions... Sample PDF
Designing Biomedical Stents for Vascular Therapy: Current Perspectives and Future Promises
Chapter 11
Yos Morsi, Zhang Li, Sheng Wang
This chapter gives an overview of heart valve diseases, their diagnostics techniques, and current and future treatments with particular emphasis on... Sample PDF
Heart Valve Diseases in the Elderly: Current Treatments and Future Directions
Chapter 12
Olof A. Lindahl, Anders Eklund, Per Hallberg
The chapter involves the description and the application of a new sensor technology called tactile resonance sensors for diagnoses of the... Sample PDF
Tactile Resonance Sensors for Detection and Diagnosis of Age-Related Diseases
Chapter 13
Athina Bakopoulou, Gabriele Leyhausen, Werner Geurtsen, Petros Koidis
Stem cell-based dental tissue regeneration is a new and exciting field that has the potential to transform the way that we practice dentistry. It... Sample PDF
Dental Tissue Engineering Research and Translational Approaches towards Clinical Application
Chapter 14
Phuc Van Pham, Loan Thi-Tung Dang, Nhung Hai Truong, Ngoc Kim Phan
In recent years, Platelet Rich Plasma (PRP) and Adipose-Derived Stem Cells (ADSCs) have been used separately for many clinical applications... Sample PDF
Can Activated Platelet Rich Plasma Combined with Adipose-Derived Stem Cells Be Used to Treat Skin Wrinkles?: A Mechanism Study
Appendix A
Appendix B
Appendix C
Appendix D
Appendix E
Appendix F
Appendix G
Appendix H
Appendix I
About the Contributors