Bone has considerable potential for repair and regeneration. In adults these events are locally regulated by cytokines. One of the cytokines that potentially plays a significant role in bone regeneration is platelet-derived growth factor. Evidence that PDGF may be an important mediator of bone regeneration stems from findings that it is stored in bone, has the capacity to stimulate bone cells, is produced by bone cells, and is generated in wound healing environments. Despite the above evidence, there have been few studies to investigate the capacity of normal human osteoblastic cells to synthesize and respond to PDGF. It is the goal of this proposal to investigate the potential role of PDGF as a bone regulatory cytokine by studying PDGF synthesis and response in vitro in normal human osteoblastic cells. In order to accomplish this objective we will establish normal human adult osteoblastic cell populations consisting of bone cell explants and cells cloned from these explants. These bone cells will be thoroughly characterized for the osteoblastic phenotype. We will investigate the synthesis of PDGF by these cells and determine which factors regulate expression of the two PDGF genes, PDGF-A and PDGF-B. We will also examine the response of bone-derived cells to each PDGF isoform, PDGF-AB, PDGF-BB, PDGF-AA. This will be studied on several levels; 125I PDGF binding, the induction of secondary messages, the induced expression of specific genes, stimulation of DNA synthesis, cellular proliferation and formation of an in vitro mineralizing matrix. And finally, we will determine if the production of PDGF and response to PDGF leads to autocrine stimulation in normal human osteoblastic cells.
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