1. Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs
- Author
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Minyong Kang, Jong Bin Choi, Yong-Mahn Han, Bumsoo Kim, Hyo Sang Do, Joonsun Lee, Han-Wook Yoo, Beom Hee Lee, and Young Hee Ju
- Subjects
TGF-β ,Beta-catenin ,Induced Pluripotent Stem Cells ,iPSCs ,Core Binding Factor Alpha 1 Subunit ,Biology ,Biochemistry ,Article ,osteogenesis ,Extracellular matrix ,Calcification, Physiologic ,Costello syndrome ,TGF beta signaling pathway ,Genetics ,medicine ,TIMP ,Humans ,HRAS ,Smad3 Protein ,Induced pluripotent stem cell ,Cells, Cultured ,beta Catenin ,Extracellular Matrix Proteins ,Osteoblasts ,Tissue Inhibitor of Metalloproteinase-1 ,Mesenchymal stem cell ,Costello Syndrome ,Osteoblast ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,β-catenin ,medicine.disease ,Alkaline Phosphatase ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,Developmental Biology ,Signal Transduction - Abstract
Summary 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 β-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances β-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 β-catenin signaling., Highlights • Enhanced p-SMAD3 signaling dysregulates ECM remodeling proteins in CS osteoblasts • Overexpression of TIMPs impairs osteogenesis of CS MSCs independent of RUNX2 • Elevated level of TIMPs reduces β-catenin activity and OSX expression • Gene correction of CS iPSCs reverts defective osteogenesis, In this article, Han and colleagues suggest new insights into the mechanisms by which mutated HRASG12S induces the bone abnormalities observed in CS patients. Furthermore, they suggest a model in which ECM remodeling proteins (MMP13, TIMP1, and TIMP2) and their related pathways (HRAS-MAPK, TGF-β, and β-catenin) help explain the impaired osteogenesis of CS MSCs.
- Published
- 2021