Friday, April 26, 2024
4/26/2024
¿ DESCRIPTION (provided by applicant): The long-term objective of this proposal is to investigate the role of zinc finger transcriptional factor, Kruppel like factor-2 (KLF2) in the regulation of osteoclastogenesis and rheumatoid arthritis (RA)-related pathogenesis. Among the cellular components monocytes play major roles in mediating progression of RA. The monocytes migrate from the peripheral blood to the arthritic joint tissues and secrete pro-inflammatory factors, and these factors in turn mediate inflammation and recruit other immune cells, which mediate differentiation of monocytes towards osteoclasts. Since it has been reported that KLF2 can induce quiescence to the immune cells and also inactivate monocytes in response to stimulation (active monocytes are required to promote osteoclastogenesis) and because our preliminary results indicate severe arthritic joint changes in KLF2 hemizygous mice (KLF2 homozygous knock out mice are embryonically lethal), we therefore hypothesize that this transcription factor may inhibit osteoclastogenesis and thereby, pathogenesis of RA. Aim1 will determine the importance of myeloid KLF2 in regulating the pathogenesis in RA. Experimental Design: Conditional gain and loss of gene function approach will be undertaken to determine the role of KLF2 in the regulation of pathogenesis in vivo. Complementary histologic, histomorphometric, immunohistochemical, and radiologic (micro CT) studies will be used to evaluate extent of the disease. Human monocytes and joint tissues from RA and healthy controls will be studied to confirm findings. Aim 2 will examine the bases for KLF2's ability to regulate osteoclastogenesis. Experimental Design: Gain- and loss-of-function approaches will be used to determine the role of KLF2 in osteoclastic differentiation. Additionally, the cross talk between KLF2 and osteoclastogenesis markers (NFATc1, NF¿B, Cathepsin K and MMP9) and osteoblastogenesis markers (RANK/RANKL, OPG, BMP2/4, and Runx2) will be determined. Human monocytes from RA and healthy controls will also be studied to confirm findings. Aim 3 will investigate whether the effects of pharmacological compound on arthritis and osteoclastogenesis are KLF2 dependent. We found that a group of pharmacological compound, such as HDAC inhibitor (HDACi) induces KLF2 expression in myeloid cells. Experimental Design: We will verify if HDACi induce KLF2 in myeloid cells in mice. Next, we will determine if the HDACi-mediated regulation of inflammation and osteoclastogenesis is KLF2- dependent using various molecular approaches (structure-functions studies, co-immunoprecipitation, and ChIP assays). The knowledge generated from this study will not only identify a novel endogenous regulator of osteoclastogenesis in RA, but also indicate newer and effective strategies to control this disease.
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