Role of CSF-1 in Osteoclast Function

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): Colony-stimulating factor 1 (CSF1) is the principal colony-stimulating factor produced by osteoblasts constitutively and in response to several hormones and cytokines. It is absolutely required for osteoclastogenesis, but its role in regulating mature osteoclast function remains unclear. In vitro, it is known to prolong mature osteoclast survival and stimulate cytoskeletal remodeling and motility. We have found that CSF1 can regulate electrolyte transporters and gene transcription in mature osteoclasts, pointing to new metabolic pathways regulated by this cytokine. Recent studies have identified CSF1 as a therapeutic target in states of pathologic bone remodeling such as bone loss associated with inflammatory arthritis and bone destruction associated with skeletal metastases. CSF1 also appears to play an important role in mediating estrogen-deficiency bone loss. Therefore, a better understanding of how CSF1 acts to regulate mature osteoclast function is clearly of physiologic and therapeutic importance. The central hypothesis of this application is that CSF1 mediates mature osteoclast function in part by modulating the activity of the small GTPase, Rac1. We postulate that Rac1 lies at the intersection of two important effector pathways, one that targets actin remodeling and a second that targets gene regulation by modulating NF?B signaling. Three Specific Aims are designed to test this hypothesis. Specific Aim 1 explores the role of two Rac isoforms, Rac1 and Rac2, in mediating CSF1's actions in osteoclasts because we have defined CSF1-dependent, non- redundant roles for these isoforms in regulating the osteoclast cytoskeleton. Breast Cancer Associated Protein 3, is a Rac-interacting protein we have recently identified in a yeast two hybrid screen using an osteoclast cDNA library. We have discovered that BCA3 regulates CSF1-induced cytoskeletal remodeling and also augments NF?B p65 signaling. In the second Specific Aim, the role of BCA3 in mediating both CSF1 and RANKL signaling will be explored. Finally, in Specific Aim 3, a genetic approach will be used to further clarify the function CSF1 in mature osteoclasts by deleting its receptor, c-fms, in these cells. In the aggregate, these studies will provide a more detailed metabolic map of CSF1's actions in mature osteoclasts, which is a current gap in the scientific database. This new information will help inform ongoing efforts to develop therapies based on the actions of CSF1 in bone.