hofstetter@dkf.unibe.ch

     Bone mass is determined by two opposite processes. Osteoblasts, cells of mesenchymal origin and sharing common precursors with chondrocytes, myocytes, adipocytes and fibroblasts, are synthesizing the components of the extracellular matrix which in turn mineralizes. Osteoclasts, which develop from the haematopoietic stem cells and belong to the monocyte/macrophage lineages, resorb the bone by dissolving the mineral and by digesting the organic part of the matrix. In the adult organism, these two processes are in balance and bone mass is preserved.
     During the past few years it has become increasingly evident that many diseases of the skeleton, which at the first glimpse have little in common, are based on similar molecular and cellular mechanisms. An inflammatory disease like rheumatoid arthritis, a disease of ageing like osteoporosis, but also surgical compli
cations like the loosening of orthopaedic joint replacements, are brought about by similar repertoires of cytokines which are released by similar cell populations and which affect similar targets. These common denominators of bone diseases give a new urgency to the efforts to elucidate and understand the role(s) of inflammatory cytokines in bone cell biology and metabolism.

     In our research group we have focused in recent years on the response of haematopoietic cells to metal alloys that are used in orthopaedic surgery. Cells of bone encounter implants either as surfaces with a specific morphology, but also as small particles which are shed from the implants, or even solubilized as metal ions in blood and interstitial fluids.  It is of significant relevance to understand, whether and how these metals induce a reaction in the recipients of the implants and how this reaction affects the longevity of the implant and as a consequence the quality of life for the patients.

     We have found that wear particles and metal surfaces exert significant stimulatory effects on the development of osteoclasts, the cells that dissolve the mineral and digest the organic matrix of bone (Sommer et al., 2005). To further analyze the effects of the immune system on the development of bone, the reactions of recipients to transplanted bones, both in isogeneic and allogeneic situations, was investigated (Egli et al., 2003; Fraitzl et al., 2001). These studies were performed with the aim to improve our understanding on the biocompatibility of bone grafts and orthopaedic implants and to assess the contributions of the inflammatory reactions to osseointegration.

     Most recently, we focused on the effects of soluble metals on the release of cytokines by cells of the monocyte/macrophage lineages and on their respective effects on the development and activation of osteoclasts. Using Low Density Gene Arrays (LDAs), we found in human monocytes a set of genes regulated by bivalent metal ions, while trivalent ions were virtually negative. It was most intriguing that the expression of growth factors and cytokines was dependent on the metal ions used in this study. For example, Co2+ and Ni2+ elicited different effects in the target cells (Jost-Albrecht & Hofstetter, 2006). The biochemical and molecular mechanisms for these effects will be the focus of further studies in this project.

     Since cytokines and growth factors are components of the haematopoietic microenvironment, we are interested in the effects of the individual components of this microenvironment on the cells of the osteoclast lineages (for years our interest was focused on the role of CSF-1 in osteoclastogenesis Rubin et al., 2000; Halasy-Nagy & Hofstetter, 1998). Of particular interest is TNFa, a major mediator of inflammation and a potent stimulator of bone resorption. Recently we found that TNFa under certain conditions can act as an inhibitor of bone resorption as well (Inauguraldissertation R Balga, 2004, “Tumor necrosis factor alpha in bone loss induced by ovariectomy and in the development of osteoclasts”). Using transgenic animals deficient in the p55TNFR, we demonstrated the dependence of the inhibitory effect on the the presence of functional receptors on osteoblasts, while the growth factor simultaneously exerted a stimulatory effect on osteoclastogenesis through a direct action on haematopoietic precursor cells (Balga et al., 2006). The molecular and biochemical characterization of the effects of TNFa on osteoclastogenesis will be a major focus in the studies of our group in the near future.
     In collaboration with M. Seitz and D. Aeberli from the Clinic of Rheumatology, Clinical Immunology and Allergy, the role of TNFa in the maintenance of osteoclast progenitors in peripheral blood of patients with Rheumatoid Arthritis and Ankylosing Spondylitis was investigated. A crucial role of TNFa in the maintenance of this precursor pool was demonstrated when we found that the application of a treatment protocol using an inactivating humanized anti-TNFa antibody significantly decreased the resorptive potential of the PBMC (Gengenbacher et al., 2008).

    Together with Frank Klenke (PI) from the Clinic of Orthopaedic Surgery at the University Hospital, Bern, CH, and the Dr. h.c. Robert Mathys Foundation, Bettlach, CH, the role of growth factors and their binding to  biomaterials on the osseointegration of CaP ceramics was investigated. Thereby, the choice of growth factors, the required amounts and the release kinetics are separately under study (Klenke et al, 2008; Wernike et al., 2010a; Wernike et al., 2010b).

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