How To Get A Global Vision Of The Mineralizing Process?
The second volume of the eBook series entitled “Frontiers between Science and Clinic in Odontology” is devoted to Bone and Dentin Phosphorylated Extracellular Matrix Proteins. Due to the increasing knowledge on extracellular matrix (ECM) proteins, either we were going to produce a non-transferable monster, occupying the whole memory of the hard derive as an eBook impossible to download, or the field had to be split into three distinct parts.
Collagen by itself constitutes an important topic. We may focus on its synthesis, structure, intracellular assembly, transport and secretion. We could also examine the mechanisms leading to the self-assembly properties within the intracellular and extracellular compartments. As an ECM molecule, sub-units interact and display an increasing diameter and elongate. Interactions of collagen with other ECM lead to fibrillation, and afterward collagen fibrils get the capacity to become mineralized. The genetic defects occurring during collagen processing are associated to bone pathologies. Many other aspects could also be considered (such as collagen as a molecule carrier, the immune reaction following collagen implantation, etc.). This would constitute by itself an incredible thick volume.
It is clear today that non-collagenous proteins are implicated in the structure of bone and dentin and that most of these molecules intervene in different types of mineralization processes. Many ECMs are not phosphorylated. This is the case at least for two extracellular matrix components, osteocalcin, and osteonectin. For many other components so far identified in the two tissues, up to now emphasis has not been put on their phosphorylation and associated potential properties. This large family includes many growth factors and the CCN family. These later have been shown to play key roles as matricellular proteins. They serve as adaptor molecules and multifunctional regulating factors connecting the cell surface and ECM. This could also constitute a large and stimulating topic for another thick volume.
Therefore, it was realistic to concentrate on the phosphorylated non-collagenous ECM proteins of bone and dentin, taking into consideration 4 reasons. Firstly, this is a group of structural molecules, which are present in the two tissues. Secondly, they are also implicated in the regulation of mineralization either as nucleators or inhibitors. Thirdly, some molecules have dual functions and are also identified as being matricellular molecules. Fourthly, there is now increasing evidences that they are implicated as signaling molecules.
The complexity of the structural role(s) is heightened by the fact that if one of the phosphorylated molecules is missing, defective bone or dentin is formed, unless compensatory mechanisms allow the formation of the tissue that displays a discrete phenotype.
Phosphorylated ECMs are signaling molecules. As an example, in the first volume, it was shown that amelogenin, which is phosphorylated in Serine 16 in the TRAP region, was both a structural protein implicated in enamel formation and mineralization, and also a signaling molecule. As amelogenin is expressed by odontoblasts and osteoblasts as an intracellular molecule, and because the two faces of this molecule were already discussed in our previous volume, deliberately we did not include amelogenin and a few other enamel proteins in this second series of chapters. However, it is a good example of the multifunctional role of molecules implicated as structural molecules in mineralized tissue formation, and also found in many other non-dental, non-mineralizing tissues for reasons that remain to be elucidated.
Clearly, there was a need for such extensive synthesis for PhD students and researchers, and a requirement for bringing altogether the present knowledge. What is presented here was widely spread in hundred and even thousand of research articles, and/or found in proceedings of international conferences which are sometimes difficult to collect. Some reviews were focusing on a whole family of ECM molecules or in some cases on a single molecule, but they never included the whole tribe of phosphorylated proteins. Doing that, we expect that a global vision of the mineralizing process will be understood by the reader.
How To Catch And Keep Co-Authors
Having this project in my mind, I turned toward my highly specialized best friends and tried to establish an ideal list of presumable volunteers. This was quite easy at the start of the project, and most of the members of the conspiracy immediately agreed to participate in the project. I was floating in the sky, happy as a cloud on a sunny day. A few colleagues apologized: they were implicated in grant applications and had no time for such a heavy task, or they just wrote a review, and were not willing to duplicate, etc. With those who did not accept, our friendship was slightly frozen, however the excuses were acceptable. Other excellent scientists were approached and eventually I came to a final list of contributors.
If I remember well, at that time I had many friends. Some months later, hunting to receive the promised chapters, my life and their life became more difficult. I received rapidly a few chapters. Later, I started to send reminders and recalls, with apparently little success. Some of my friends answered that the chapter was in good tracks and will be completed soon. Computer problems arose and some never received nor answered my alarm mails. As the dead line was approaching, I begged them to send their chapter urgently. Of course, if I have asked less famous contributors, it would be easier to get quickly their contributions, because they had plenty of time. Unfortunately, as only the bests among the bests were involved in this project, and most of them were very busy, implicated in new experiments, into important academic functions, comities or grant applications and in addition, in international conferences. Finally after sending hundred of mails (and probably more), I was fortunate to receive all the excellent chapters of this eBook.
One question still remains: how many friends are still my friends? Presumably, next time when I will start with the project of another book, I will know the answer.
The eBook is now complete and ready for publication. I am proud of the quality of the chapters produced by my collaborators. The different parts are at the top level, and even better that I could expect, confirming that the bests were selected to share their science in the requested topics.
The Ebook Content
In order to cover the different facets of the area, the organization of the eBook follows a rather simple order.
Evolution (Chapter 1): The first chapter reports on the origin and evolution of bone and dentin phosphoproteins. Jean-Yves Sires and Kazuhiko Kawasaki reviewed the structures and sites where the ancestral tissues were formed. Then, they describe the cells implicated in the synthesis of ECM molecules, and how evolution influences cell differentiation and secretion. The molecules, which are expressed, are modified during evolution, and display structural changes. The two authors are focusing on ECM domains, which are either deleted or well conserved, and doing so, they show which are the ancestor molecules and how they are shared in the different mineralized tissues.
Cells producing bone and dentin (Chapters 2, 3):
We then move to the cells producing bone and dentin, osteoblasts and osteocytes for the former and odontoblasts for the later. Jeff Gorski was asked to focus on the changes occurring between bone progenitors, bone-lining cells, functional osteoblasts and osteocytes, reviewing the molecules implicated in bone ECM synthesis and mineralization. Deliberately, he was asked to restrain his chapter to the cells involved in bone matrix formation, leaving osteoclasts out of the field although it is clear that complex interactions are occurring between osteoblasts and osteoclasts. However, we were willing to focus mostly on the cellular events leading to the synthesis and secretion of bone phosphorylated EMC molecules.
In chapter 3, we analyze the implication of odontoblasts in the formation of different types of dentin. We follow the functional evolution between pre-odontoblasts, polarized odontoblasts and senescent cells, pointing out at the anatomical changes occurring during this cascade of events. Morphological differences between the peripheral and circumpulpal dentin formation, and the specific location of the secretory materials contribute to get a better understanding of three different types of dentinogenesis. We also review the up-take and fate of precursors of ECM molecules and their implication in dentin mineralization.
Genes, transcription factors and signaling pathways- dentin genetic pathologies (Chapters 4-7): Mary MacDougall et al., Charles Sfeir et al., Shuo Chen et al., and Tim Wright have clarified these major points, in 4 specific outstanding chapters. We move from the coding genes to the intracellular processing and the mechanisms regulating intracellular phosphorylation. Finally, the last chapter of this section is devoted to the consequences of genetic alterations on teeth pathologies.
The SIBLING family (Chapters 8- 14):
The protein structures and post-translational modification constitute the first target of this third part (Y. Yamakoshi). Then, in order to elucidate the functions played by the daughter molecules after cleavage (DSPP, DSP, DPP), Suzuki & Kulkarni learned lessons from mouse models. To make the picture complete, DMP1, BSP, osteopontin and MEPE were analyzed. The composition, processing and respective functions of members of the SIBLING family were reviewed by the best experts in the field (for DMP1 and DMP-1 KO mice Ramachandran & Anne George, and Jerry Feng et al.; Harvey Goldberg and Graem Hunter wrote a report on BSP. Bernhard Ganss & Anil Bansal wrote a superb review on osteopontin. This fascinating multi-facetted protein was involved not only in biological and pathologic mineralizations, but is also implicated in inflammation, immune response and cancer progression. Finally, Peter Rowe dissected the different domains of MEPE, and their implication in bone defects. All of these authors produced outstanding contributions, providing structural analysis of the molecules, describing the functions of their different domains and the impact on mineralization.
The mechanisms implicated in biomineralizations (Chapters 15, 16):
The contribution of phosphorylated proteins to the mineralization processes is well recognized but need to be analyzed in the context of biomimetic interactions between specific domains with the chemical elements of the periodic system. How proteins induce the initial formation of crystals? The transition between organic molecules and the initial crystals formation is occurring? How the terminal size and shape of crystals are stimulated or inhibited by ECM molecules located at close environment? Arthur Veis & Stuart Stock wrote an important contribution to the nucleation part (Chapter 15), and this was followed by the contribution of Adele Boskey, who covered the part devoted to factors that contribute to the shape and growth of crystals (Chapter 16).
Phospholipids/lipoproteins and mineralization, the role of MMPs (Chapters 17, 18):
In addition to phosphorylated proteins, phospholipids are present in the ECM, probably as lipoproteins. M. Goldberg et al. covered this topic and showed that these molecules play role(s) in bone and dentin mineralization. At the onset of mantle dentin formation, these molecules are associated with the mineralization processes resulting from the formation/mineralization of matrix vesicles. Phospholipids are associated to the intercollagen spaces in predentin and as needle-like or crystal ghosts coating mineralized collagen fibrils in the intertubular dentin. Finally, they participate in the formation of an amorphous network in the peritubular dentin. Despite histochemical observations failed to reveal any relationship between phospholipids and mineralization, a chemically induced mutation of the sphingomyelin phosphodiesterase 3 provides evidences of an interaction between the ECM molecule and bone mineralization (osteogenesis imperfecta) and dentin pathology (dentinogenesis imperfecta/dentin dysplasia) (chapter 17).
Finally, metalloproteases are instrumental in regulating normal growth, mineralization and remodeling of mineralized tissues. This last part was remarkably covered by Leo Tajerdhane et al. (chapter 18).
At the end of these chapters, we can expect that the readers may have a complete view on the regulation of cells implicated in osteogenesis and dentinogenesis, on the synthesis and secretion of ECM molecules and extracellular regulations. This series of chapters should allow insights in the mechanisms directing the biomineralization of skeletal structures.
Under The Auspices Of Janus, The Two-Faced God, And Proteus, The God Who Never Answer To Our Questions
All the chapters of this eBook were written under the auspices of two ancient gods. We can invoke Janus, a roman god, and Proteus, a Greek god, son of Poseidon, the so-called “old man of the sea”.
Janus is a two-faced god, providing simultaneously two diverging answers to the same question: as an answer, is it yes or no, is it the true or an error, is it peace or war? Gates and doors symbolize the binary god. He is looking toward the past and the future. And if we ask in order to get a clear-cut idea if a molecule is a promoter or an inhibitor, depending on the concentration, the heath or any other parameters, we got two contradictory answers. Can we reconcile antagonistic views formulated by the ancient Chinese as being the yin and the yang? The aim of the researcher is to merge the two different facets, to build a unified reality. But probably, this is only a wish.
The other god, Proteus is synonym of versatile, mutable, and adaptable. He can foretell the future, but will change his shape to avoid having to answer direct questions. As a scientist, he would be able to publish controversial studies, without giving a final solution to any questioning. However, he will answer only to someone who is capable of capturing him. This is exactly the difficult task that we have tried to handle in this eBook, with more or less success.
May the two-faces of the god and the difficulties encountered to catch the true help young and old researchers to get an acceptable answer to their questions.
Finally I want to acknowledge the help of our two gifted PhD students working in the group 5 of our INSERM Unit. During the preparation of this eBook, they were implicated in this task both as scientists and as mastering computers. During all these years, they gradually became friends, co-workers and co-authors and I have to acknowledge their help and extensive participation. All my warm thanks to you, Sasha Dimitrova-Nakov and Yassine Harichane, UMR S 747 INSERM & University Paris Descartes.
UMR S 747 INSERM & University Paris Descartes
Biomédicale des Saints- Pères