STING Contributes to Abnormal Bone Formation Induced by Deficiency of DNase II in Mice.

Abstract

OBJECTIVE:

Cytosolic DNA sensors detect microbial DNA and promote type I interferon (IFN) and proinflammatory cytokine production through the adaptor stimulator of IFN genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. This study sought to identify the role of STING in regulating bone formation and to define the bone phenotype and its pathophysiologic mechanisms in arthritic mice double deficient in DNase II and IFN-α/β/ω receptor (IFNAR) (DNase II-/- /IFNAR-/- double-knockout [DKO] mice) compared with controls.

METHODS:

Bone parameters were evaluated by micro-computed tomography and histomorphometry in DKO mice in comparison with mice triple deficient in STING, DNase II, and IFNAR and control mice. Cell culture techniques were employed to determine the 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 proinflammatory cytokines that would be expected to induce bone loss in the skeleton of DKO mice, the results, paradoxically, demonstrated an accumulation of bone in the long bones and spleens, sites of erythropoiesis and robust DNA accrual. In addition, factors promoting osteoblast recruitment and function were induced. Deficiency of STING significantly inhibited bone accrual.

CONCLUSION:

These data reveal a novel role for cytosolic DNA sensor pathways in bone in the setting of autoimmune disease. The results 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 human autoimmune diseases.

• Authors: Rebecca Baum, Shruti Sharma, Jason M Organ, Christopher Jakobs, Veit Hornung, David B Burr, Ann Marshak-Rothstein, Katherine A Fitzgerald, Ellen M Gravallese
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 69 Issue 2 Pg. 460-471 (Feb 2017) ISSN: 2326-5205 [Electronic] United States
• PMID: 27740718 (Publication Type: Journal Article)
• Copyright: © 2016, American College of Rheumatology.

Chemical References

• Membrane Proteins
• Sting1 protein, mouse
• Endodeoxyribonucleases
• deoxyribonuclease II

Topics

• Animals
• Bone and Bones (abnormalities, enzymology)
• Endodeoxyribonucleases (deficiency)
• Female
• Male
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout