ArticleStem cell reports2021
Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs.
Article in Stem cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 12 citations in OpenAlex.
- Therapeutic effects of lomerizine on vasculopathy in Fabry disease.Scientific reports · 2025Article
- Fasudil alleviates the vascular endothelial dysfunction and several phenotypes of Fabry disease.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes.Frontiers in endocrinology · 2023Review
- Aberrant Cortical Layer Development of Brain Organoids Derived from Noonan Syndrome-iPSCs.International journal of molecular sciences · 2022Article
- Increased osteoclastogenesis contributes to bone loss in the Costello syndromeFrontiers in cell and developmental biology · 2022Article
- Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy.Frontiers in genetics · 2021Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
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Abstract
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.
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