Collagen Gene Col2a1 Research Articles

Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study.

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-mo treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20mg/kg open label. Therefore, only results from the 2, 8, and 20mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular volumetric bone mineral density (vBMD) from baseline at month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro-finite element (microFE)-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12mo, there was a significant increase in mean (SE) failure load in the 20mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p>05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.

Differential network analysis reveals the key role of the ECM-receptor pathway in α-particle-induced malignant transformation

Space particle radiation is a major environmental factor in spaceflight, and it is known to cause body damage and even trigger cancer, but with unknown molecular etiologies. To examine these causes, we developed a systems biology approach by focusing on the co-expression network analysis of transcriptomics profiles obtained from single high-dose (SE) and multiple low-dose (ME) α-particle radiation exposures of BEAS-2B human bronchial epithelial cells. First, the differential network and pathway analysis based on the global network and the core modules showed that genes in the ME group had higher enrichment for the extracellular matrix (ECM)-receptor interaction pathway. Then, collagen gene COL1A1 was screened as an important gene in the ME group assessed by network parameters and an expression study of lung adenocarcinoma samples. COL1A1 was found to promote the emergence of the neoplastic characteristics of BEAS-2B cells by both in vitro experimental analyses and in vivo immunohistochemical staining. These findings suggested that the degree of malignant transformation of cells in the ME was greater than that of the SE, which may be caused by the dysregulation of the ECM-receptor pathway.

Evaluation of the safety and efficacy of cosmetics ingredient Spherulites Paeony Superior Retinol.

Microencapsulation of hydroxypinacolone retinoate (HPR) can improve its application in cosmetics. To investigate the safety and efficacy of Spherulites Paeony Superior Retinol, a HPR microcapsule containing 5%-10% peony seed oil, 0.01%-1% epigallocatechin gallatyl glucoside (ECGG), and 0.1%-1% HPR. The safety of Spherulites Paenoy Superior Retinol was evaluated with zebrafish embryo self-rotation irritation test and developmental toxicity test. SymRenew™ HPR was used as a reference. The skin care efficacies of Spherulites Paenoy Superior Retinol were evaluated using zebrafish embryos covering antioxidation, anti-inflammation, blood circulation, whitening, wound healing, skin barrier protection, Type I collagen, elastin, and 5α-reductase genes expression activities. The irritation test revealed that 250 μg/mL Spherulites Paenoy Superior Retinol did not, while 20 μg/mL SymRenew™ HPR significantly (p < 0.05) increased zebrafish embryo self-rotation frequency. The developmental toxicity test found the teratogenicity index (half lethal concentration/half toxicity concentration) of Spherulites Paenoy Superior Retinol and SymRenew™ HPR were 1.9 and 3.1, respectively. The efficacy analysis results showed that 5 μg/mL Spherulites Paenoy Superior Retinol significantly (p < 0.05) exerted 7.1% anti-ROS, 20% anti-inflammation, 14% enhanced blood circulation, 10% suppressed melanin synthesis, 9% enhanced tail fin regeneration, 72% elicited skin barrier protection activity, enhanced the expression of Type I collagen genes col1a1, col1a2, and col1a2 by 34%, 51%, and 42%, respectively, and elastin gene elna by 46%, and suppressed the expression of 5α-reductase genes srd5a1, srd5a2a, and srd5a2b by 52%, 15%, and 30%, respectively. This study demonstrated that Spherulites Paenoy Superior Retinol is a safe cosmetic ingredient with multi-skin care efficacies.

Abstract P07: Identification of the unique preleukemic bone marrow niche in acute myeloid leukemia

Abstract P07: Identification of the unique preleukemic bone marrow niche in acute myeloid leukemia

Identification of a family with van der Hoeve's syndrome harboring a novel COL1A1 mutation and generation of patient-derived iPSC lines and CRISPR/Cas9-corrected isogenic iPSCs.

Van der Hoeve's syndrome, also known as osteogenesis imperfecta (OI), is a genetic connective tissue disorder characterized by fragile, fracture-prone bone and hearing loss. The disease is caused by a gene mutation in one of the two type I collagen genes COL1A1 or COL1A2. In this study, we identified a novel frameshift mutation of the COL1A1 gene (c.1607delG) in a family with OI using whole-exome sequencing, bioinformatics analysis and Sanger sequencing. This mutation may lead to the deletion of a portion of exon 23 and the generation of a premature stop codon in the COL1A1 gene. To further investigate the impact of this mutation, we established two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of OI patients carrying a novel mutation in the COL1A1 gene. Osteoblasts (OB) derived from OI-iPSCs exhibited reduced production of type I collagen and diminished ability to differentiate into osteoblasts. Using a CRISPR-based homology-directed repair strategy, we corrected the OI disease-causing COL1A1 novel mutations in iPSCs generated from an affected individual. Our results demonstrated that the diminished expression of type I collagen and osteogenic potential were enhanced in OB induced from corrected OI-iPSCs compared to those from OI-iPSCs. Overall, our results provide new insights into the genetic basis of Van der Hoeve's syndrome and highlight the potential of iPSC technology for disease modeling and therapeutic development.

Bioinformatics Analysis Identifies Key Genes in the Effect of Resistance Training on Female Skeletal Muscle Aging.

Resistance training is used to combat skeletal muscle function decline in older adults. Few studies have been designed specific for females, resulting in very limited treatment options for skeletal muscle atrophy in aging women. Here, we analyzed the gene expression profiles of skeletal muscle samples from sedentary young women, sedentary older women, and resistance-trained older women, using microarray data from public database. A total of 45 genes that were differentially expressed during female muscle aging and reversed by resistance training were identified. Functional and pathway enrichment analysis, protein-protein interaction network analysis, and receiver operating characteristic analysis were performed to reveal the key genes and pathways involved in the effects of resistance training on female muscle aging. The collagen genes COL1A1, COL3A1, and COL4A1 were identified important regulators of female muscle aging and resistance training, by modulating multiple signaling pathways, such as PI3 kinase-Akt signaling, focal adhesions, extracellular matrix-receptor interactions, and relaxin signaling. Interestingly, the expression of CDKN1A and TP63 were increased during aging, and further upregulated by resistance training in older women, suggesting they may negatively affect resistance training outcomes. Our findings provide novel insights into the molecular mechanisms of resistance training on female muscle aging and identify potential biomarkers and targets for clinical intervention.

Molecular genetic determinants of stress urinary incontinence in women: Prospective comparative study

Aim. To identify the molecular genetic determinants of stress urinary incontinence (UI) in women.&#x0D; Materials and methods. A comparative study involving 120 women was conducted. Group 1 (main group) included 80 women with UI. Group 2 (comparison group) included 40 women without UI. Statistic data processing was performed using the Excel software package, SPP Statistics 22.0, Statistica for Windows 10 (TIBCO Software Inc., Palo Alto, CA, USA). The mean and standard deviation were reported for quantitative variables with a normal distribution. The statistical hypotheses on the absence of intergroup differences for quantitative variables with normal distribution were verified using Student's test. The absolute and relative values (in percent) were reported for qualitative variables. The chi-square test was used to verify the statistical hypotheses.&#x0D; Results. Molecular genetic predictors of UI in women are the carriage of polymorphisms of the estrogen receptor gene ESR1:-351_G and the type I collagen gene COL1A1:1546_T. These polymorphisms can be considered as genotypes of "risk" since their carriage is associated with an increased risk of UI.&#x0D; Conclusion. Genetically determined disorders of the estrogen receptor function and type I collagen synthesis can be one of the essential mechanisms of stress incontinence occurrence. Studying molecular genetic determinants of stress incontinence can provide a deeper understanding of its pathogenetic mechanisms and develop a personalized approach to surgical correction.

A Rare Pathogenic Variant in the SERPINF1 Gene in Association with Early-Onset Severe Presentation of Autosomal Recessive Type of Osteogenesis Imperfecta VI: A Case Report

Osteogenesis imperfecta (OI) refers to a group of genetic disorders with the typical clinical presentation of increased bone fragility. More than 90% of OI cases have an underlying genetic mutation in the collagen genes COL1A1 or COL1A2. However, there are now 22 different recognized OI subtypes based on the underlying gene implicated. OI type VI is caused by pathogenic variants in the serine proteinase inhibitor clade F (SERPINF1) gene. In this case study, the patient was a 4-year-old female, born in a consanguineous family, with a history of delayed gross motor milestones and recurrent fractures after trivial trauma since the age of 8 months. The results of skeletal surveys and bone scans indicated that the patient suffered from OI. To confirm the diagnosis, we performed a next-generation sequencing (NGS) analysis of genes implicated in OI using the TruSight One NGS Panel. Bioinformatics analysis showed the presence of a rare pathogenic variant in exon 7 of the SERPINF1 gene in a homozygous state (NM_002615.5:c.907C&gt;T; NP_002606.3:p.Arg303Ter; ClinVar submission ID: SUB10491966). The variant results in the termination of the polypeptide chain at position 303. Targeted capillary sequencing confirmed the presence of this variant in a homozygous state in the patient and in heterozygous state for both parents. Additionally, the patient’s younger sibling, aged 10 months, harbored the variant in a homozygous state. The sibling started bisphosphonate therapy and did not suffer any fractures in over 2 years after initiating the therapy. The etiological genetic diagnosis helped provide genetic counseling to the family. This highlights the utility of NGS for the confirmation of a clinical analysis in cases where alterations in multiple genes can result in similar clinical presentation.

160-LB: Age-Related Adipose Tissue Fibrosis and Neuropathy in the Genetically Diverse HET3 Mouse

Changes in adipose tissue's extracellular matrix, as with fibrosis, inhibits the tissue's ability to shrink and expand as needed, resulting in sheer stress on adipocytes and chronic inflammation, as well as decreased insulin sensitivity. With aging, a state of metabolic dysregulation and increased incidence of insulin resistance, we have observed a reduction in adipose innervation. This ‘adipose neuropathy' likely poses a physiological challenge for tissue metabolic function and glucose homeostasis, as has been observed in adipose denervation studies. Using second-harmonic generation label-free imaging of adipose collagen and advanced image co-localization techniques, we found that obese adipose tissue exhibits higher co-localization of nerves with collagen fibers, indicating that changes in tissue fibrosis may tie mechanistically with tissue neuropathy. We compared C57BL/6J mice with the more genetically diverse HET3 mouse model that is used by the NIA's intervention testing program, to investigate age-related neuropathy and adipose fibrosis. We found that HET3 mice displayed mitigated neuropathy phenotypes in skin, muscle and adipose, compared to inbred C56BL/6J mice. Tissue fibrosis was significantly increased with age in subcutaneous and visceral white adipose depots of both strains of mice. Using birefringence imaging, we found that the relative distribution of type I / thick filament collagen increased with age while type III / thin filament collagen decreased. Gene expression by qPCR revealed significant increases in collagen genes Col1a1, Col3a1, and Col5a1 in adipose with age. Despite its success as a longevity treatment, the mTOR inhibitor rapamycin had little to no effect on reducing or preventing the onset of neuropathy in HET3 aged mice, and importantly it worsened the fibrotic phenotype with increased type 1 collagen in adipose. Together, we found that rapamycin's longevity effects are uncoupled from healthspan producing effects, with detrimental impacts on adipose fibrosis that may impact age-related insulin resistance. Disclosure J. Willows: None. G. Mishra: None. M. Blaszkiewicz: None. K. L. Townsend: Other Relationship; Neuright, Inc. Funding American Heart Association (AHA) Collaborative Sciences Award (18CSA34090028)

Prenatal inflammation enhances antenatal corticosteroid-induced fetal lung maturation.

Respiratory complications are the major cause of morbidity and mortality among preterm infants, which is partially prevented by the administration of antenatal corticosteroids (ACS). Most very preterm infants are exposed to chorioamnionitis, but short- and long-term effects of ACS treatment in this setting are not well defined. In low-resource settings, ACS increased neonatal mortality by perhaps increasing infection. We report that treatment with low-dose ACS in the setting of inflammation induced by intraamniotic lipopolysaccharide (LPS) in rhesus macaques improves lung compliance and increases surfactant production relative to either exposure alone. RNA sequencing shows that these changes are mediated by suppression of proliferation and induction of mesenchymal cellular death via TP53. The combined exposure results in a mature-like transcriptomic profile with inhibition of extracellular matrix development by suppression of collagen genes COL1A1, COL1A2, and COL3A1 and regulators of lung development FGF9 and FGF10. ACS and inflammation also suppressed signature genes associated with proliferative mesenchymal progenitors similar to the term gestation lung. Treatment with ACS in the setting of inflammation may result in early respiratory advantage to preterm infants, but this advantage may come at a risk of abnormal extracellular matrix development, which may be associated with increased risk of chronic lung disease.

MRTF-A mediates the activation of COL1A1 expression stimulated by multiple signaling pathways in human breast cancer cells

Deposition of type I collage in ECM is an important property of various fibrotic diseases including breast cancer. The excessive expression of type I collagen contributes to the rigidity of cancer tissue and increases the mechanical stresses which facilitate metastasis and proliferation of cancer cells via the activation of TGF-β signaling pathway. The increased mechanical stresses also cause the compression of blood vessels and result in hypoperfusion and impaired drug delivery in cancer tissue. Additionally, type I collage functions as the ligand of α2β1-integrin and DDR1/2 receptors on the membrane of cancer cells to initiate signal transduction leading to metastasis. The expression of type I collage in cancer cells is previously shown to be inducible by TGF-β however the detailed mechanism by which the synthesis of type I collagen is regulated in breast cancer cells remains unclear. Herein, we report that MRTF-A, a co-activator of SRF, is important for the regulation of type I collagen gene COL1A1 in breast cancer cells. MRTF-A physically interacted with the promoter of COL1A1 to facilitate histone acetylation and RNA polymerase II recruitment. The RhoC-ROCK signaling pathway which controls the nuclear localization of MRTF-A regulated the transcription of COL1A1 in human breast cancer cells. TGF-β and Wnt signaling increased the expression of both MRTF-A and COL1A1. Furthermore, depletion of MRTF-A abolished the upregulation of COL1A1 in response to the TGF-β or Wnt signaling, indicating the importance of MRTF-A in the synthesis of type I collagen in breast cancer. Given the crucial roles of type I collagen in the formation of metastasis-prone and hypoperfusion microenvironment, MRTF-A would be a potential target for the development of anti-breast cancer activities.

Impact of maternal high fat diet on hypothalamic transcriptome in neonatal Sprague Dawley rats.

Maternal consumption of a high fat diet during early development has been shown to impact the formation of hypothalamic neurocircuitry, thereby contributing to imbalances in appetite and energy homeostasis and increasing the risk of obesity in subsequent generations. Early in postnatal life, the neuronal projections responsible for energy homeostasis develop in response to appetite-related peptides such as leptin. To date, no study characterises the genome-wide transcriptional changes that occur in response to exposure to high fat diet during this critical window. We explored the effects of maternal high fat diet consumption on hypothalamic gene expression in Sprague Dawley rat offspring at postnatal day 10. RNA-sequencing enabled discovery of differentially expressed genes between offspring of dams fed a high fat diet and offspring of control diet fed dams. Female high fat diet offspring displayed altered expression of 86 genes (adjusted P-value<0.05), including genes coding for proteins of the extra cellular matrix, particularly Collagen 1a1 (Col1a1), Col1a2, Col3a1, and the imprinted Insulin-like growth factor 2 (Igf2) gene. Male high fat diet offspring showed significant changes in collagen genes (Col1a1 and Col3a1) and significant upregulation of two genes involved in regulation of dopamine availability in the brain, tyrosine hydroxylase (Th) and dopamine reuptake transporter Slc6a3 (also known as Dat1). Transcriptional changes were accompanied by increased body weight, body fat and body length in the high fat diet offspring, as well as altered blood glucose and plasma leptin. Transcriptional changes identified in the hypothalamus of offspring of high fat diet mothers could alter neuronal projection formation during early development leading to abnormalities in the neuronal circuitry controlling appetite in later life, hence priming offspring to the development of obesity.

Leukocytic Toll-Like Receptor 2 Deficiency Preserves Cardiac Function And Reduces Fibrosis In Sustained Pressure Overload

An involement of Toll-like receptor 2 (TLR2) has been established in cardiac dysfunction after acute myocardial infarction; however, its role in chronic pressure overload is unclear. We sought to evaluate the role of TLR2 in cardiac hypertrophy, fibrosis and dysfunction in sustained pressure overload. We induced pressure overload via transverse aortic constriction (TAC) in TLR2−/− and wild type (WT) mice, and followed temporal changes over 8 weeks. Despite similar increases in heart weight, left ventricular (LV) ejection fraction (EF) and diastolic function (mitral E/A ratio) were preserved in TLR2−/− mice but impaired in WT mice following TAC. TAC produced less LV fibrosis in TLR2−/− mice associated with lower mRNA levels of collagen genes (Col1a1 and Col3a1) and lower protein level of TGFbeta1, compared to WT mice. Following TAC, the influx of macrophages and CD3 T cells into LV was similar between TLR2−/− and WT mice, whereas levels of cyto/chemokines were lower in the heart and plasma in TLR2−/− mice. TLR2−/− bone marrow-derived cells protected against LVEF decline and fibrosis following TAC. Our findings show that leukocytic TLR2 deficiency protects against LV dysfunction and fibrosis probably via a reduction in inflammatory signaling in sustained pressure overload.

Liver epithelioid progenitor cells derived from fetal Luxi bovine alleviate liver fibrosis.

Liver epithelioid progenitor cells (LEPCs) have important roles in liver therapy because of their hepatic differentiation potency in vitro and in vivo. Despite many researches on humans, mice, and rats, equivalent progenitor cells derived from bovine are relatively rare. The purpose of our current study is to characterize bovine LEPCs, and research on the cure potency of this heteroplastic progenitor cells on mice liver fibrosis. We have used collagenase IV digesting and differential adhesion method to isolate slabstone shape, EpCAM, LGR5, NCAM1 and SOX9 positive progenitor cells from fetal Luxi bovine liver. When cultured in hepatic differentiation media containing 20ng/ml Oncostatin M, LEPCs can differentiate into hepatocytes in vitro. After 4weeks of intravenous tail vein injection into CCl4-injured mouse liver, LEPCs engrafted into liver parenchyma, differentiated into ALB positive hepatocytes, and could alleviate liver fibrosis through down regulating fibrosis genes-Tgfb1 and α-SMA as well as decreasing expression of collagen gene Col1a1, Col3a1, and Col4a1, and regain liver function by recovering ALT and AST. Our findings provided a useful tool for studying liver development in vitro, new cell resource for heterograft on mouse liver diseases, and a new platform for researches on immune rejection of heterogeneous cell transplantation.

Luteolin-7-diglucuronide attenuates isoproterenol-induced myocardial injury and fibrosis in mice.

Myocardial injury and ensuing fibrotic alterations impair normal heart architecture and cause cardiac dysfunction. Oxidative stress has been recognized as a key player in the pathogenesis of cardiac injury and progression of cardiac dysfunction, and promoting fibrosis. In the current study we investigated whether luteolin-7-diglucuronide (L7DG), a naturally occurring antioxidant found in edible plants, could attenuate isoproterenol (ISO)-induced myocardial injury and fibrosis in mice and the underlying mechanisms. Myocardial injury and fibrosis were induced in mice via injection of ISO (5 mg·kg-1·d-1, ip) for 5 or 10 d. Two treatment regimens (pretreatment and posttreatment) were employed to administer L7DG (5-40 mg·kg-1·d-1, ip) into the mice. After the mice were euthanized, morphological examinations of heart sections revealed that both L7DG pretreatment and posttreatment regimens significantly attenuated ISO-induced myocardial injury and fibrosis. But the pretreatment regimen caused better protection against ISO-induced myocardial fibrosis than the posttreatment regimen. Furthermore, L7DG pretreatment blocked ISO-stimulated expression of the genes (Cyba, Cybb, Ncf1, Ncf4 and Rac2) encoding the enzymatic subunits of NADPH oxidase, which was the primary source of oxidant production in mammalian cells. Moreover, L7DG pretreatment significantly suppressed ISO-stimulated expression of collagen genes Col1a1, Col1a2, Col3a1, and Col12a1 and non-collagen extracellular matrix genes fibrillin-1, elastin, collagen triple helix repeat containing 1 and connective tissue growth factor. In addition, L7DG pretreatment almost reversed ISO-altered expression of microRNAs that were crosstalking with TGFβ-mediated fibrosis, including miR-29c-3p, miR-29c-5p, miR-30c-3p, miR-30c-5p and miR-21. The current study demonstrated for the first time that L7DG is pharmacologically effective in protecting the heart against developing ISO-induced injury and fibrosis, justifying further evaluation of L7DG as a cardioprotective agent to treat related cardiovascular diseases.

Mutational characterization of the P3H1/CRTAP/CypB complex in recessive osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.

Autosomal Recessive Osteogenesis Imperfecta: A Puzzle for Bone Formation, Structure and Function

Bone is a composite material that resembles reinforced concrete. The collagen matrix plays the role of reinforcement, whereas hydroxyapatite crystals are cementing material. Collagen fibers are responsible for the tensile strength of bones and prevent fractures from extending; the mineral phase is able to withstand compaction loads. A right balance of these two parts synergistically provides the required stiffness for bone. Collagen abnormalities, such as reduced amount, disturbed composition, defects in structure and/or supramolecular organization as well as insufficient or defective mineralization, lead to osteogenesis imperfecta (OI), also known as brittle bone disease. Until recently, mutations in the type I collagen genes COL1A1 and COL1A2 were the only known causes of the disease, which cover about 90 % of diagnosed OI. Within the last decade, we have witnessed a burst in the identification of new OI mutations in other genes. Here we summarize our knowledge of these mutations and their impact on bone quality.

COL2A1 Is Frequently Mutated in Chondrosarcoma

Abstract The major cartilage collagen gene COL2A1 is mutated in 37% of chondrosarcomas.

Frequent mutation of the major cartilage collagen gene COL2A1 in chondrosarcoma

Chondrosarcoma is a heterogeneous collection of malignant bone tumors and is the second most common primary malignancy of bone after osteosarcoma. Recent work has identified frequent, recurrent mutations in IDH1 or IDH2 in nearly half of central chondrosarcomas. However, there has been little systematic genomic analysis of this tumor type, and, thus, the contribution of other genes is unclear. Here we report comprehensive genomic analyses of 49 individuals with chondrosarcoma (cases). We identified hypermutability of the major cartilage collagen gene COL2A1, with insertions, deletions and rearrangements identified in 37% of cases. The patterns of mutation were consistent with selection for variants likely to impair normal collagen biosynthesis. In addition, we identified mutations in IDH1 or IDH2 (59%), TP53 (20%), the RB1 pathway (33%) and Hedgehog signaling (18%).

Bone Morphogenetic Protein–Inducer Tilorone Identified by High-Throughput Screening Is Antifibrotic In Vivo

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis and very few therapeutic options. On the molecular level, patients with IPF have increased amounts of the bone morphogenetic protein (BMP) inhibitor gremlin in their lungs, which results in decreased BMP signaling, and an increase in transforming growth factor-β signaling. Based on these findings, we hypothesized that restoration of the impaired BMP signaling would offer a novel strategy for the prevention of fibrosis progression or for the treatment of pulmonary fibrosis. We used reporter cell lines and high-throughput screening of a chemical compound library as an approach to finding molecules that increase BMP signaling in lung epithelial cells, without increasing transforming growth factor-β signaling. The most promising candidate drug was analyzed further by studying its effects on BMP target gene expression, Smad protein phosphorylation, and a mouse model of silica-induced pulmonary fibrosis. The most promising drug candidate, tilorone, induced BMP signaling in the reporter cells and increased the expression of BMP-7 and a BMP target gene, Id3, in lung epithelial A549 cells. In a mouse model of pulmonary fibrosis, tilorone decreased lung hydroxyproline content and the expression of collagen genes Col1A1 and Col3A1. Mice treated with tilorone showed markedly decreased histological changes, compared with untreated mice. These findings indicate that tilorone has biologically significant antifibrotic properties.