Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs

Choi, Jong Bin; Lee, Joonsun; Kang, Minyong; Kim, Bumsoo; Ju, Young Hee; Sang, Hyo; Yoo, Han‐Wook; Lee, Beom Hee; Han, Yong‐Mahn

doi:10.1016/j.stemcr.2021.06.007

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…Nevertheless, we cannot exclude that CS Hras mutations do not affect their proper function, either by inducing senescence or through other unknown pathomechanisms. Hras is known to affect collagen, extracellular matrix deposition and elastin ( Yamagata et al, 1996 ; Hinek et al, 2000 ; Choi et al, 2021 ), and thus influence bone strength leading to frailty and increased risk for fractures. Therefore, to confirm that Hras does not affect bone strength in mice where bone loss is absent, a functional assay such as 3-point bending test ( Deckard et al, 2017 ; Prodinger et al, 2018 ) would provide valuable information ( Jameson and De Groot, 2010 ; Biver, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, increased RAS signalling due to HRAS G12S mutation impaired osteoblast differentiation and osteogenesis without affecting mesenchymal stem cells. ( Choi et al, 2021 ). In contrast to HRAS, KRAS hyperactivation increases bone mass by increasing mouse osteoblast progenitor cell proliferation via MAPK and AKT pathways without affecting mature osteoblasts ( Ge et al, 2009 ; Li et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…To date, the underlying causes of osteoporosis in CS patients and CS mouse models are largely unknown. Furthermore, there are some contradicting reports between clinical data suggesting an increased bone resorption and in vitro studies using CS iPSCs-differentiated osteoblasts that revealed that osteogenesis is affected (Choi et al, 2021). Therefore, in this study, utilizing the CS mouse model harbouring an Hras G12V germline mutation (Schuhmacher et al, 2008) we aimed at proving that these mice recapitulate the patients' phenotype and undergo bone loss, as well as to identify which bone cell type is driving the bone phenotype when Hras is mutated.…”

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confidence: 98%

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Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model

Nandi

Chennappan²,

Andrasch³

et al. 2022

Front. Cell Dev. Biol.

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RAS GTPases are ubiquitous GDP/GTP-binding proteins that function as molecular switches in cellular signalling and control numerous signalling pathways and biological processes. Pathogenic mutations in RAS genes severely affect cellular homeostasis, leading to cancer when occurring in somatic cells and developmental disorders when the germline is affected. These disorders are generally termed as RASopathies and among them Costello syndrome (CS) is a distinctive entity that is caused by specific HRAS germline mutations. The majority of these mutations affect residues 12 and 13, the same sites as somatic oncogenic HRAS mutations. The hallmarks of the disease include congenital cardiac anomalies, impaired thriving and growth, neurocognitive impairments, distinctive craniofacial anomalies, and susceptibility to cancer. Adult patients often present signs of premature aging including reduced bone mineral density and osteoporosis. Using a CS mouse model harbouring a Hras G12V germline mutation, we aimed at determining whether this model recapitulates the patients’ bone phenotype and which bone cells are driving the phenotype when mutated. Our data revealed that Hras G12V mutation induces bone loss in mice at certain ages. In addition, we identified that bone loss correlated with an increased number of osteoclasts in vivo and Hras G12V mutations increased osteoclastogenesis in vitro. Last, but not least, mutant osteoclast differentiation was reduced by treatment in vitro with MEK and PI3K inhibitors, respectively. These results indicate that Hras is a novel regulator of bone homeostasis and an increased osteoclastogenesis due to Hras G12V mutation contributes to bone loss in the Costello syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

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Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model

Nandi

Chennappan²,

Andrasch³

et al. 2022

Front. Cell Dev. Biol.

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“…Choi et al found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of Costello syndrome (CS) MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. Specifically, enhanced TIMP1/2 expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via inactivation of wnt/β-catenin signaling ( Choi et al, 2021 ). Compared with normal nucleus pulposus (NP) tissues, intervertebral disc degeneration (IDD) samples exhibited higher levels of circular RNA derived from TIMP2 (circ-TIMP2) expression levels.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Ning

Diao

et al. 2022

Front. Genet.

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The mechanism of environmental factors in Kashin–Beck disease (KBD) remains unknown. We aimed to identify single nucleotide polymorphisms (SNPs) and protein alterations of selenium- and T-2 toxin–responsive genes to provide new evidence of chondrocytic damage in KBD. This study sampled the cubital venous blood of 258 subjects including 129 sex-matched KBD patients and 129 healthy controls for SNP detection. We applied an additive model, a dominant model, and a recessive model to identify significant SNPs. We then used the Comparative Toxicogenomics Database (CTD) to select selenium- and T-2 toxin–responsive genes with the candidate SNP loci. Finally, immunohistochemistry was applied to verify the protein expression of candidate genes in knee cartilage obtained from 15 subjects including 5 KBD, 5 osteoarthritis (OA), and 5 healthy controls. Forty-nine SNPs were genotyped in the current study. The C allele of rs6494629 was less frequent in KBD than in the controls (OR = 0.63, p = 0.011). Based on the CTD database, PPARG, ADAM12, IL6, SMAD3, and TIMP2 were identified to interact with selenium, sodium selenite, and T-2 toxin. KBD was found to be significantly associated with rs12629751 of PPARG (additive model: OR = 0.46, p = 0.012; dominant model: OR = 0.45, p = 0.049; recessive model: OR = 0.18, p = 0.018), rs1871054 of ADAM12 (dominant model: OR = 2.19, p = 0.022), rs1800796 of IL6 (dominant model: OR = 0.30, p = 0.003), rs6494629 of SMAD3 (additive model: OR = 0.65, p = 0.019; dominant model: OR = 0.52, p = 0.012), and rs4789936 of TIMP2 (recessive model: OR = 5.90, p = 0.024). Immunohistochemistry verified significantly upregulated PPARG, ADAM12, SMAD3, and TIMP2 in KBD compared with OA and normal controls (p < 0.05). Genetic polymorphisms of PPARG, ADAM12, SMAD3, and TIMP2 may contribute to the risk of KBD. These genes could promote the pathogenesis of KBD by disturbing ECM homeostasis.

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“…Both in vitro and in vivo studies were performed in NF1, showing a dysregulated activity in cells of the osteoblastic and osteoclastic lineages (Choi et al, 2017; Choi et al, 2021; Kim et al, 2019; Stevenson, Yan, et al, 2011). For example, in vitro studies on induced pluripotent stem cells (iPSCs) from an individual with CFCS that were differentiated into mesenchymal stem cells (MSCs) showed an altered osteogenic differentiation, with reduced activity of ALP and impaired mineralization (Choi et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Bone health in RASopathies

Stevenson

Viscogliosi

Leoni

2022

American J of Med Genetics Pt C

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The RASopathies are a group of disorders due to pathogenic variants in genes involved in the Ras/MAPK pathway, many of which have overlapping clinical features (e.g., neurofibromatosis type 1, Costello syndrome, cardiofaciocutaneous syndrome and Noonan syndrome) including musculoskeletal manifestations. Osteopenia and osteoporosis are reported in many of the RASopathies suggesting a shared pathogenesis. Even though osteopenia and osteoporosis are often detected and fractures have been reported, the clinical impact of bone mineralization defects on the skeleton of the various syndromes is poorly understood. Further knowledge of the role of the Ras/MAPK pathway on the bone cellular function, and more detailed musculoskeletal phenotyping will be critical in helping to develop therapies to improve bone health in the RASopathies.

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Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs

Cited by 10 publications

References 51 publications

Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model

Increased osteoclastogenesis contributes to bone loss in the Costello syndrome Hras G12V mouse model

Genetic Variants and Protein Alterations of Selenium- and T-2 Toxin-Responsive Genes Are Associated With Chondrocytic Damage in Endemic Osteoarthropathy

Bone health in RASopathies

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