ESTROGEN REGULATION OF CYTOKINE RESPONSIVENESS IN BONE--OSTEOCLASTOGENESIS

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

Description (Taken from the application): The goal of this project is to examine the role that the cytokine interleukin-1 (IL-1) has in estrogen withdrawal induced bone loss. The central hypothesis is that ovariectomy enhances IL-1 activity in the microenvironment of bone. which, in turn, causes enhanced bone resorption. This result may occur because stromal/osteoblastic cells are induced to increase their Production of signals that enhance osteoclast activity and/or because IL-1 directly signal hematopoietic/osteoclastic cells to increase net osteoclast formation and/or bone resorption. Studies planned for this renewal will test both these hypotheses and determine if either or both are correct. Based on the results of the studies in Aim 1, which examine in vivo the relative roles of stromal/osteoblastic and hematopoietic/osteoclastic cells in the effects of IL-1 on ovariectomy-induced bone loss, we will perform additional experiments that are described in Aims 2 and 3, which explore the mechanisms by which IL-1 influences ovariectomy-induced bone loss. Detailed Specific Aims are the following: aim 1. Determine if the failure of ovariectomy to cause bone loss in IL-1 R1 KO mice is mediated by the hematopoietic/osteoclastic cell and/or stromal/osteoblastic cells; aim 2. Determine the role of stromal/osteoblastic cells in the failure of ovariectomy to cause bone loss in IL-1R1KO mice; aim 3. Determine the role of hematopoietic cells in the failure of ovariectomy to cause bone loss in IL-R1K0 mice.