Session Title: ACR Plenary Session II: Discovery 2014
Session Type: Plenary Sessions
Background/Purpose: Cytosolic DNA sensors detect viral and bacterial DNA, inducing inflammatory cytokines and type I IFNs via the adaptor stimulator of interferon genes (STING) to clear infection. The STING pathway also responds to endogenous DNA from dying cells and contributes to autoimmune disease. We have identified a potentially important role for cytosolic DNA sensor pathways in bone by studying a mouse that develops inflammatory polyarthritis and articular erosions in the setting of DNA accrual. In this model, DNA accumulates in macrophages due to deletion of the lysosomal endonuclease DNaseII and is detected by cytosolic sensors that signal through STING. Type I IFNs in DNaseII-/- mice lead to anemia-related embryonic lethality; thus co-deletion of the type I IFN receptor is required (DNaseII/IFN-IR double deficient, (DKO) mouse). We investigated the impact of DNA and of the STING pathway in bone in this model of autoimmune disease.
Methods: STING-/- mice were intercrossed with DKO mice to generate STING/DNaseII/IFN-IR triple knock out (TKO) mice. uCT was performed on TKO, DKO, and control femurs from 6-16 month-old mice. Mesenchymal colony forming unit (CFU) assays were used to determine the number of osteoblast precursor cells in bone. uCT was performed on femurs from 6 month-old STING-/- and littermate controls. Finally, RNA from wild type (WT) osteoblasts was analyzed for the expression of cytosolic DNA sensors. To determine the potential for osteoblasts to respond directly to DNA, MC3T3 osteoblast-lineage cells were transfected with poly(dA:dT) and RNA was analyzed by qPCR.
Results: Inflammatory cytokines in the DKO model would be expected to induce bone loss in the axial skeleton, as well as articular erosions. Paradoxically, we found that bone accumulates in long bones, with significant replacement of the marrow cavity by 16 months. CFU assays demonstrate increased osteoblast precursor numbers, and osteoid is also significantly increased in DKO compared to controls (13,881 vs. 424 µm2, p=0.02). Surprisingly, ectopic bone forms in DKO spleens, a site of DNA accrual in macrophages. We thus sought to define the contribution of cytosolic DNA sensor pathways to bone accrual. STING deficiency almost completely abrogates both arthritis and bone accrual in the spleen and long bones of DKO mice (BV/TV: Het = 0.44%, DKO = 11.47%, TKO = 1.99%, p<0.02 compared to DKO). STING also contributes to bone homeostasis, independent of DNaseII deficiency, as revealed by uCT performed on femurs from STING-/- and littermate controls (BV/TV: STING-/- = 1.39%, WT = 0.62%, p=0.011). Furthermore, cytosolic DNA sensors are expressed in osteoblasts and expression of several sensors is increased in osteoblasts upon transfection with a DNA ligand.
Conclusion: The STING pathway plays a role in bone remodeling in situations of DNA accrual as well as in bone homeostasis. Cytosolic DNA sensors are expressed in differentiating osteoblasts and expression is upregulated by DNA. These findings have relevance to SLE and other autoimmune diseases in which DNA plays a pathogenic role. Discovery of new pathways linking bone and the immune system may identify new targets for the treatment of bone loss in inflammatory autoimmune diseases.
J. M. Organ,
D. B. Burr,
K. A. Fitzgerald,
E. M. Gravallese,
Eli Lilly and Company,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-sting-pathway-regulates-bone-remodeling-in-a-model-of-autoimmune-disease/