Rebecca Baum, Shruti Sharma, Jason M. Organ, Christopher Jakobs, Veit Hornung, David B. Burr, Ann Marshak-Rothstein, Katherine A. Fitzgerald, Ellen M. Gravallese
Objective: Cytosolic DNA sensors detect microbial DNA and promote type I interferon and pro-inflammatory cytokine production through the adaptor stimulator of interferon genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. We identified a novel role for STING in bone in arthritic DNase II/IFNaR double deficient (DKO) mice, and sought to define the bone phenotype in these mice and to address mechanism.
Methods: Bone parameters were evaluated in DKO, STING/DNaseII/IFNaR triple deficient and control mice by microcomputed tomography and histomorphometry. Cell culture techniques were employed to determine parameters of osteoclast and osteoblast differentiation and function. Nanostring and Affymetrix array analyses were performed to identify factors promoting ectopic bone formation.
Results: Despite the expression of pro-inflammatory cytokines that would be expected to induce bone loss in the skeleton in DKO mice, we demonstrate the paradoxical accumulation of bone in the long bones and spleen, sites of erythropoiesis and robust DNA accrual, as well as the induction of factors promoting osteoblast recruitment and function. STING deficiency significantly inhibits this bone accrual.
Conclusions: These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. We demonstrate the requirement of an intact STING pathway for bone formation in this model, a finding that may have relevance to autoimmune diseases in which DNA plays a pathogenic role. Identification of pathways linking innate immunity and bone could reveal novel targets for the treatment of bone abnormalities in autoimmune diseases.