ADAMs, Osteoclastogenesis and Bone Destruction in the Loosening of the Totally Replaced Hip

Total hip replacement is the golden standard treatment for severe osteoarthritis refractory for conservative treatment. Aseptic loosening and osteolysis are the major long-term complications after total hip replacement. Foreign body giant cells and osteoclasts are locally formed around aseptically loosening implants from precursor cells by cell fusion. When the foreign body response is fully developed, it mediates inflammatory and destructive host responses, such as collagen degradation. In the present study, it was hypothesized that the wear debris and foreign body inflammation are the forces driving local osteoclast formation, peri-implant bone resorption and enhanced tissue remodeling. Therefore the object was to characterize the eventual expression and the role of fusion molecules, ADAMs (an abbreviation for A Disintegrin And Metalloproteinase, ADAM9 and ADAM12) in the fusion of progenitor cells into multinuclear giant cells. For generation of such cells, activated macrophages trying to respond to foreign debris play an important role. Matured osteoclasts together with activated macrophages mediate bone destruction by secreting protons and proteinases, including matrix metalloproteinases (MMPs) and cathepsin K. Thus this study also assessed collagen degradation and its relationship to some of the key collagenolytic proteinases in the aggressive synovial membrane-like interface tissue around aseptically loosened hip replacement implants. ADAMs were found in the interface tissues of revision total hip replacement patients. Increased expression of ADAMs at both transcriptional and translational levels was found in synovial membrane-like interface tissue of revision total hip replacement (THR) samples compared with that in primary THR samples. These studies also demonstrate that multinucleate cell formation from monocytes by stimulation with macrophage-colony stimiulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) is characterized by time dependent changes of the proportion of ADAMs positive cells. This was observed both in the interface membrane in patients and in two different in vitro models. In addition to an already established MCS-F and RANKL driven model, a new virally (parainfluenza 2) driven model (of human salivary adenocarcinoma (HSY) cells or green monkey kidney (GMK) cells) was developed to study various fusion molecules and their role in cell fusion in general. In interface membranes, collagen was highly degraded and collagen degradation significantly correlated with the number of local cells containing collagenolytic enzymes, particularly cathepsin K. As a conclusion, fusion molecules ADAM9 and ADAM12 seem to be dynamically involved in cell-cell fusion processes and multinucleate cell formation. The highly significant correlation between collagen degradation and collagenolytic enzymes, particularly cathepsin K, indicates that the local acidity of the interface membrane in the pathologic bone and soft tissue destruction. This study provides profound knowledge about cell fusion and mechanism responsible for aseptic loosening as well as increases knowledge helpful for prevention and treatment.

Paradise Reconsidered : A Study of the Ophite Myth and Ritual and their Relationship to Sethianism

This thesis examines the mythology in and social reality behind a group of texts from the Nag Hammadi and related literature, to which certain leaders of the early church attached the label, Ophite, i.e., snake people. In the mythology, which essentially draws upon and rewrites the Genesis paradise story, the snake's advice to eat from the tree of knowledge is positive, the creator and his angels are demonic beasts and the true godhead is depicted as an androgynous heavenly projection of Adam and Eve. It will be argued that this unique mythology is attested in certain Coptic texts from the Nag Hammadi and Berlin 8502 Codices (On the Origin of the World, Hypostasis of the Archons, Apocryphon of John, Eugnostos, Sophia of Jesus Christ), as well as in reports by Irenaeus (Adversus Haereses 1.30), Origen (Contra Celsum 6.24-38) and Epiphanius (Panarion 26). It will also be argued that this so-called Ophite evidence is essential for a proper understanding of Sethian Gnosticism, often today considered one of the earliest forms of Gnosticism; there seems to have occurred a Sethianization of Ophite mythology. I propose that we replace the current Sethian Gnostic category by a new one that not only adds texts that draw upon the Ophite mythology alongside these Sethian texts, but also arranges the material in smaller typological units. I also propose we rename this remodelled and expanded Sethian corpus "Classic Gnostic." I have divided the thesis into four parts: (I) Introduction; (II) Myth and Innovation; (III) Ritual; and (IV) Conclusion. In Part I, the sources and previous research on Ophites and Sethians will be examined, and the new Classic Gnostic category will be introduced to provide a framework for the study of the Ophite evidence. Chapters in Part II explore key themes in the mythology of our texts, first by text comparison (to show that certain texts represent the Ophite mythology and that this mythology is different from Sethianism), and then by attempting to unveil social circumstances that may have given rise to such myths. Part III assesses heresiological claims of Ophite rituals, and Part IV is the conclusion.