Rheumatoid arthritis (RA) is a debilitating chronic disease that leads to focal loss of bone in inflamed joints. Osteoclast-mediated resorption is one mechanism for loss of articular bone. However, data from our laboratory demonstrate a defect in the maturation of bone-forming osteoblasts (OBs) at sites of articular bone loss (erosions), with an accompanying inhibition in the formation of mineralized bone at sites of inflammation. OB differentiation and function is dependant upon positive signaling through the Bone Morphogenic Protein (BMP) and Wingless-type (Wnt) signaling pathways. We have identified expression of inhibitors of OB differentiation and function at sites of bone erosion in the murine serum transfer arthritis (STA) model. Expression of BMP3, an inhibitor of pro-osteogenic BMP2 signaling, and of two Wnt signaling pathway inhibitors, Dickkopf1 (DKK1) and secreted Frizzled related-protein1 (sFRP1), is induced at sites of erosion, implicating these factors in the inhibition of OB maturation and function in RA. In this grant we will evaluate the contribution of two intersecting pathways by testing the hypothesis that inflammation in RA synovium leads to modifications in the BMP and Wnt signaling pathways that inhibit OB function, and thereby accelerates focal articular bone loss.
In Aim 1, we will test the hypothesis that BMP3 plays a unique role in the inhibition of OB function at sites of erosion, and acts through modulation of Wnt signaling. The process of bone erosion will be evaluated in BMP3 deficient and control littermate mice with STA by histologic quantitation, quantitation of articular bone by microCT, and dynamic histomorphometry. The regulation of Wnt signaling by BMP3 will be determined in focused SuperArray assays in vitro.
Aim 2 will test the hypothesis that enhanced Wnt signaling is protective in focal bone erosion in RA due to augmentation of OB-mediated bone formation. This will be achieved by promoting Wnt signaling in two animal models of arthritis by inhibiting GSK-3 (Part A) or by specifically blocking DKK1 activity (Part B). TNFa, a critical cytokine in RA pathogenesis, is an inhibitor of OB differentiation and function in vitro, and induces DKK1 in synovial fibroblasts.
In Aim 3, the effects of TNFa on expression of BMP3 and Wnt antagonists in cell types found within arthritic lesions will be determined in vitro, and potential interactions between the BMP and Wnt signaling pathways in these cell types will also be determined. Cellular sources of these factors will be identified in animal models in vivo. These studies are designed to identify novel targets for the augmentation of bone formation in RA.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that destroys bone locally within affected joints, leading to patient morbidity and long-term disability. Although removal of bone is one mechanism leading to bone loss in joints, evidence presented in this grant application demonstrates that there is a suppression of bone formation in affected joints because of inhibition of the maturation and function of bone forming osteoblast cells. The experiments proposed are designed to identify new targets for the augmentation of bone formation at sites of joint-based bone loss in arthritis.
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