期刊
JOURNAL OF IMMUNOLOGY
卷 203, 期 5, 页码 1356-1368出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1900354
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资金
- Japan Science and Technology Agency
- Ministry of Education, Culture, Sports, Science and Technology of Japan [24115004]
- Japan Agency for Medical Research and Development [JP17ek0109100h0003, JP18ek0109387h0001]
- Kato Memorial Trust for Nambyo Research
- Japan Society for the Promotion of Science Core to Core Program
- Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy [EXC2151 - 390873048, TRR237]
- Grants-in-Aid for Scientific Research [24115004] Funding Source: KAKEN
Singleton-Merten syndrome (SMS) is a type I interferonopathy characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, and psoriasis. A missense mutation in IFIH1 encoding a cytoplasmic viral RNA sensor MDA5 has recently been identified in the SMS patients as well as in patients with a monogenic form of lupus. We previously reported that Ifih1(gs/+) mice express a constitutively active MDA5 and spontaneously develop lupus-like nephritis. In this study, we demonstrate that the Ifih1(gs/+) mice also exhibit SMS-like bone abnormalities, including decreased bone mineral density and thin cortical bone. Histological analysis revealed a low number of osteoclasts, low bone formation rate, and abnormal development of growth plate cartilages in Ifih1(gs/+) mice. These abnormalities were not observed in Ifih1(gs/+). Mavs(-/-) and /Ifih1(gs/+). Ifnar1(-/-) mice, indicating the critical role of type I IFNs induced by MDA5/MAVS-dependent signaling in the bone pathogenesis of Ifih1(gs/+) mice, affecting bone turnover. Taken together, our findings suggest the inhibition of type I IFN signaling as a possible effective therapeutic strategy for bone disorders in SMS patients.
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