Singleton-Merten Syndrome-like Skeletal Abnormalities in Mice with Constitutively Activated MDA5

The Journal of Immunology : Official Journal of the American Association of Immunologists
Nobumasa SodaTakashi Fujita

Abstract

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 Ifih1gs/+ mice express a constitutively active MDA5 and spontaneously develop lupus-like nephritis. In this study, we demonstrate that the Ifih1gs/+ 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 Ifih1gs/+ mice. These abnormalities were not observed in Ifih1gs/+ ・Mavs-/- and Ifih1gs/+ ・Ifnar1-/- mice, indicating the critical role of type I IFNs induced by MDA5/MAVS-dependent signaling in the bone pathogenesis of Ifih1gs/+ 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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Citations

Mar 24, 2020·American Journal of Medical Genetics. Part a·Jaime Vengoechea, Janette DiMonda
Oct 30, 2020·International Immunology·Ahmed Abu TayehTakashi Fujita
Nov 10, 2020·International Immunology·Hideo OnizawaTakashi Fujita
Feb 13, 2021·Cardiovascular Research·Magnus Bäck, Jean-Baptiste Michel
Jul 1, 2021·American Journal of Medical Genetics. Part a·Elio AssafAli Darwich
Jul 15, 2021·Journal of Ophthalmology·Jasmine Y SerpenLev Prasov
Nov 26, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kojiro MatsushitaHiromi Miyoshi

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