Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced b-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances b-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of b-catenin signaling.

The purpose of this study was to facilitate home visits to assess the current rate of child abuse in order to provide an agenda for the early detection and prevention of child abuse and neglect in Korea. Methods: For this retrospective descriptive research, 20 public health centers were selected, 1,991 families were visited and 2,680 children were assessed. Results: We found 415 cases (15.5%) of potential abuse and 7 cases (0.3%) of actual abuse. The greatest risk group was to children age 4 to 6 years. According to the HOME Inventory, there were 17 infants (5.8%) presenting a potential risk for child abuse and neglect. Conclusion: Visitation screening is highly recommended for prevention in the high-risk preschool age group.