Singleton-Merten Syndrome-like Skeletal Abnormalities and MDA5

September 01, 2019


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

Singleton-Merten syndrome (SMS) is a rare multisystem disorder characterized by systemic interferon signature, dental dysplasia, aortic calcification, skeletal abnormalities, and glaucoma, and psoriasis. MDA5 G821S mutant mice that were obtained by ENU mutagenesis express a constitutively active MDA5, exhibit systemic interferon signature and spontaneously develop lupus-like nephritis (Funabiki et al 2014). Soda et al demonstrated that the MDA5 mutant mice also exhibit SMS-like bone abnormalities, including decreased bone mineral density and thin cortical bone. In the MDA5 mutant mice, the dendritic cells and macrophage lineage cells, including osteoclast precursors, produce IFN-β through constitutive MDA5 signaling, resulting in the impairment of osteoclast differentiation. Osteoblast function is not intrinsically affected by MDA5 signaling but is extrinsically affected by exogenous IFN-β. The impaired balance of bone formation and resorption causes low bone turnover, leading to abnormal bone development in this SMS-model mouse. The deletion of the type I IFN receptor dramatically rescues these abnormalities, suggesting that the inhibition of type I IFN signaling as a possible therapeutic strategy for bone disorders in SMS patients.


Prof. Hiroki Kato
Institute for Cardiovascular Immunology