Cellular modeling for abnormal osteogenesis of mesenchymal stem cells derived from Costello syndrome-iPSCs

Abstract

Costello syndrome (CS) is an autosomal dominant disorder caused by the HRAS mutations. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we represent that dysregulated remodeling proteins of extracellular matrix (ECM) contribute to impaired osteogenesis in CS-iPSCs during osteogenic differentiation. Although iPSCs derived from CS-patients (CS-iPSCs) normally developed to mesenchymal stem cells (MSCs), CS-MSCs showed defective osteogenesis with decreased alkaline phosphatase activity and lower mineralization. We found that hyper-activated SMAD3 signaling led to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1 and TIMP2 in osteogenic differentiation of CS-MSCs. The β-catenin signaling was also down-regulated in CS-MSCs during osteogenic differentiation. Knock-down of TIMPs induced normal differentiation of CS-MSCs into osteoblasts and up-regulation of β-catenin signaling in a RUNX2-independent manner. Our findings demonstrate that enhanced TIMPs by hyper-activated SMAD3 signaling impair osteogenic development of CS-MSCs through inactivation of β-catenin signaling.