Singleton-Merten syndrome (SMS) is an autosomal dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma and psoriasis. Missense mutations in IFIH1 encoding MDA5 and DDX58 encoding RIG-I have recently been identified in SMS families. Both RIG-I and MDA5 are well known as intracellular viral sensors that trigger the induction of antiviral interferons and inflammatory cytokines. We had previously established Ifih1gs/+ mice bearing an MDA5 mutation that causes the spontaneous development of lupus-like nephritis. In addition, these mutant mice displayed elevated type I interferons (IFNs), TNF-α and IL-6 production in multiple organs and possessed fragile limb bones, exhibiting phenotype similar to that of SMS. This study aimed to reveal how constitutive activation of MDA5 physiologically affects bone metabolism in these mutant mice.
Ifih1gs/+ mice exhibited 60% decrease in body weights compared to their WT littermates. Micro-CT analysis revealed developmental bone abnormalities in the Ifih1gs/+ mice, including decreased bone mineral density and thin cortical bone. Histological analysis showed 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, suggesting the importance of type I IFNs by MDA5-MAVS signaling. We also found that Ifih1gs/+ mouse bone marrow cells cultured in the presence of M-CSF and RANKL for osteoclast differentiation showed impaired differentiation despite the presence of TNF-α and IL-6, enhancers of osteoclast differentiation.
These results indicate that the constitutive activation of MDA5 induces type I IFNs in Ifih1gs/+ mice bone, which affects osteoclast differentiation, bone formation by osteoblasts and chondrocytes in growth plate cartilage, leading to abnormal bone development. Our findings also suggest that inhibitors of type I IFN signaling may be an effective therapeutic strategy for bone disease in SMS patients.