Inhibition of signaling cascades in osteoblast differentiation and fibrosis
Krause, C.
Citation
Krause, C. (2011, October 5). Inhibition of signaling cascades in osteoblast differentiation
Preface
’Don’t underestimate the value of doing nothing, of just going along, listening to all the things you can’t hear, and not bothering.’
Winnie the Pooh
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Scope of investigations
The basis of the presented investigations in this book is the modulation of signal in- ducers and their respective activated signaling cascades through intrinsic antagonistic feedback- and/or feed forward-loops.
In particular, signal inducers of the transforming growth factor-β superfamily were investigated on their impact on tissue development and maintenance. Thereby, the main focus lies on a group of proteins that are commonly known as bone morpho- genetic proteins (BMPs). Due to their wide impact, Dr. H. Reddi recently proposed a more suitable name to this group of cytokines: body morphogenetic proteins. The distinct terminology is also reflected in this book. Not only does this book discuss the impact of BMP signal modulation on osteoblast differentiation (Part I), it also focuses on BMPs as potential inducers of signaling drifts in fibrotic traits (Part II). Interest- ingly, BMPs can relay signals with different outcomes. They can be signal triggers themselves as investigated in the case of osteoblast differentiation, but they can also arrest signaling cascades, as shown for TGF-β induced fibrosis.
Up to date, more than fifteen different BMPs are known. One aim of this book is to biochemically characterize different BMPs on their potential to relay signals and how this signals can be governed to yield a specific medical benefit.
It is well known that BMPs are tightly regulated on diverse interfaces throughout the cell. Thereby, the presented investigations focus on innate extracellular signaling modulators, as well as on synthetic small molecule inhibitors that have the potential to facilitate the development of new treatment strategies of certain human diseases.
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Outline of this thesis
The work presented in this book comprises four years of research at the Leiden Univer- sity Medical Center (The Netherlands), and discusses my perceptions and conclusions on the biochemical role of BMPs and their modulators in a medical background.
The self-contained parts can be summarized as follows:
PART I
Chapter 1 gives an introduction to the basics of osteoblast differentiation and dis- cusses in this respect the impact of relevant signaling cascades.
Chapter 2 gives an introduction to the bone morphogenetic protein inhibitor noggin.
Chapter 3 describes new scientific data on the identification of a key residue medi- ating bone morphogenetic protein resistance to noggin inhibition.
Chapter 4 gives an introduction to the osteocyte derived negative regulator of bone formation – sclerostin.
Chapter 5 describes new scientific data on the dual role of sclerostin as a bone mor- phogenetic protein and Wnt antagonist.
Chapter 6 discusses the impact of sclerostin and noggin on osteoblast differentiation (based on Chapter 1-5).
PART II
Chapter 7 gives an introduction to signaling cascades in fibrotic trait such as Dupuytren’s Disease.
Chapter 8 describes new scientific data on treatment strategies for Dupuytren’s Dis- ease.
Chapter 9 discusses the possible role of small pharmacological molecule inhibitors for the treatment of Dupuytren’s Disease (based on Chapter 7-8).
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