DETERMINING OSTEOBLAST/BLOOD CELL ADHESION MECHANISMS

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Hematopoietic stem cell differentiation occurs in direct proximity to osteoblasts within the bone marrow cavity. Despite this striking affiliation, surprisingly little is known about the precise cellular and molecular impact of osteoblasts on the bone marrow microenvironment. Recently, we have shown that human osteoblasts I) support the growth of primitive human hematopoietic progenitors in long term in vitro cultures and ii) that human osteoblasts produce a variety of cytokine mRNAs. To date, no known cytokine alone or in combination can account for all of these activities. In addition, we have observed a tight-adhesion between osteoblasts and hematopoietic cells. To fully characterize the unique contributions that osteoblasts make to the hematopoietic microenvironment we now propose to identify which cell adhesion molecules are utilized by normal human hematopoietic bone marrow progenitor cells (CD34+) in their adhesion to osteoblasts in vitro. In the future, we will determine whether inflammatory mediators or the maturational status of hematopoietic cells alters their adhesion to osteoblasts. This knowledge, along with our work in identifying novel osteoblast-derived hematopoietic factors, will uniquely position us for further investigations of osteoblast-supported hematopoiesis. These investigations will be useful in reducing the morbidity and mortality associated with bone marrow transplantation procedures by enhancing the production of blood cells, the treatment of choice for diverse bone marrow failure syndromes including several of the leukemias. Finally alveolar bone loss, regardless of its initiation, is ultimately mediated by osteoblast-osteoclast interactions. We hypothesize that by delineating the mechanisms utilized in by CD34+ cells to adhere to osteoblasts may be similar to the mechanisms utilized by osteoblasts to localize and/or activated osteoclastic bone resorption. As such, the mechanisms identified here may prove useful as potential new therapies for the prevention of oral tissue loss.