Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice

Abstract

<p>Multiple synostoses syndrome (SYNS) is a disease characterized by the fusion of multiple joints. Unfortunately, the underlying and critical signaling pathways of this disorder remain poorly understood. Given the pivotal role of Wnt/��-catenin signaling in skeletal development and the key regulatory effect of Axin1 and Axin2 in the ��-catenin pathway, limb mesenchymal stem cell (MSC) specific <i>Axin1</i> conditional KO (cKO) mice and <i>Axin1</i>/<i>Axin2</i> double KO (dKO) mice were generated to explore their involvement in joint formation. Abnormalities, such as developmental defects in joints and fusions in multiple joint tissues were observed in both <i>Axin1</i> cKO and <i>Axin1</i>/<i>Axin2</i> dKO mice, which resemble to the characteristics of human SYNS disease including synostoses of carpal and tarsal bones, as well as ankylosis of elbow joint and knee joint. Administration of ��-catenin or BMP inhibitor significantly reversed the joint fusion phenotype in <i>Axin1</i> cKO mice. Our findings suggest that Axin1 plays a key role in joint formation by inhibiting ��-catenin-BMP signaling and could potentially serve as a therapeutic target for SYNS.</p>