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Background The role of type I collagen, composed of collagen type I alpha 1 (COL1A1) and collagen type I alpha 2 (COL1A2), has been studied in several cancers. However, the expression of COL1A1 and COL1A2 in malignant, premalignant, and normal gastric tissues and their clinical significances in gastric cancer have not been elucidated. Methods Real-time quantitative PCR was performed in 55 malignant, 27 premalignant, and 19 normal tissues to measure COL1A1 and COL1A2 messenger RNA (mRNA) expression, and the correlations between COL1A1 and COL1A2 expression and clinicopathological parameters and patients’ survival rate were analyzed. Results We found that COL1A1 mRNA expression was significantly upregulated in premalignant and malignant tissues than in normal tissues, whereas COL1A2 mRNA expression was significantly higher in malignant tissues than in premalignant and normal tissues. Moreover, COL1A1 expression was unrelated to clinicopathological parameters, while COL1A2 expression was positively related to tumor size and depth of invasion. Besides, higher COL1A1 and COL1A2 expression levels were related to lower overall survival. Conclusions We find that COL1A1 might have its potential as a monitoring factor to screen early gastric cancer, and COL1A1 and COL1A2 might predict poor clinical outcomes in gastric cancer patients.

The carapace of the Chinese soft-shelled turtle (Pelodiscus sinensis) is rich in collagen and stands as a crucial economic trait for assessing its quality, as well as a key indicator for selective breeding. However, current studies on the mechanisms underlying collagen deposition in the carapace remain severely limited, significantly hindering progress in selective breeding. Here, the Col1a2 gene of P. sinensis was molecularly characterized for the first time. Analysis of gene structure, phylogenetic tree, and amino acid sequence homology revealed that Col1a2 is relatively conserved among tetrapods but divergent from fishes. Collinearity analysis identified the BET1-COL1A2-CASD1-SGCE gene block shared across all 14 representative vertebrates and found that the Col1a2 is located on the Z chromosome of Thamnophis elegans. Tissue expression analysis showed that Col1a1 was highly expressed in the heart, gonad, and lung. Additionally, Col1a1 expression levels markedly increased during carapace development, exhibiting a strongly positive correlation with the changes in collagen content of the carapace. In situ hybridization results revealed strong signal for the Col1a2 transcripts in fibroblasts of the dermal layer of P. sinensis carapace. Knockdown of the Col1a2 gene in the carapace cells of P. sinensis significantly reduced collagen content. Transcriptome analysis following Col1a2 knockdown identified several differentially expressed genes associated with collagen deposition, including Fbln2, IL-11, and Rspo4, as well as significantly enriched pathways such as the JAK-STAT signaling pathway, the apelin signaling pathway, and the Hippo signaling pathway. Our findings offer a molecular basis for elucidating the mechanisms of collagen deposition in the carapace of P. sinensis, while also supplying a potential target for the selective breeding of collagen-rich strains of P. sinensis.

Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proα1(I) and proα2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype–phenotype relationships emerge for each chain. One‐third of the mutations that result in glycine substitutions in α1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691–823 and 910–964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril–matrix interactions. Recurrences at the same site in α2(I) are generally concordant for outcome, unlike α1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In α2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype–phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events. Hum Mutat 28(3), 209–221, 2007. Published 2006 Wiley‐Liss, Inc.

SummaryOsteogenesis imperfecta (OI) is a genetic disease with an estimated prevalence of 1 in 13,500 and 1 in 9700. The classification into subtypes of OI is important for prognosis and management. In this study, we established a clinical severity prediction model depending on multiple features of variants in COL1A1/2 genes.IntroductionNinety percent of OI cases are caused by pathogenic variants in the COL1A1/COL1A2 gene. The Sillence classification describes four OI types with variable clinical features ranging from mild symptoms to lethal and progressively deforming symptoms.MethodsWe established a prediction model of the clinical severity of OI based on the random forest model with a training set obtained from the Human Gene Mutation Database, including 790 records of the COL1A1/COL1A2 genes. The features used in the prediction model were respectively based on variant-type features only, and the optimized features.ResultsWith the training set, the prediction results showed that the area under the receiver operating characteristic curve (AUC) for predicting lethal to severe OI or mild/moderate OI was 0.767 and 0.902, respectively, when using variant-type features only and optimized features for COL1A1 defects, 0.545 and 0.731, respectively, for COL1A2 defects. For the 17 patients from our hospital, prediction accuracy for the patient with the COL1A1 and COL1A2 defects was 76.5% (95% CI: 50.1–93.2%) and 88.2% (95% CI: 63.6–98.5%), respectively.ConclusionWe established an OI severity prediction model depending on multiple features of the specific variants in COL1A1/2 genes, with a prediction accuracy of 76–88%. This prediction algorithm is a promising alternative that could prove to be valuable in clinical practice.

Summary Rare genetic variants in genes previously described to be involved in bone monogenic disorders were identified in postmenopausal women split into two groups according to extreme bone mineral density (BMD) values and lumbar spine Z-scores. A pathogenic variant in COL1A2 gene found in a woman with low BMD highlights the overlap between osteogenesis imperfecta and osteoporosis, which may share their genetic etiology. Other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis. Purpose We aimed to evaluate whether extreme values of bone mineral density (BMD) in a population-based cohort of postmenopausal women (BARCOS) could be determined by rare genetic variants in genes related to monogenic bone disorders. Methods A panel of 127 genes related to different skeletal phenotypes was designed. Massive sequencing by targeted capture of these genes was performed in 104 DNA samples from those women of the BARCOS cohort that exhibited the highest (HZ group) and lowest (LZ group) LS Z-scores, ranging from + 0.70 to + 3.80 and from − 2.35 to − 4.26, respectively. 5’UTR, 3’UTR, splice region, missense, nonsense, and short indel variants with MAF < 0.01 were annotated with CADD version 1.6 and considered in the analysis. Results After filtering those variants with CADD > 25 and present only in one of the groups (either LZ or HZ), six variants were detected, most of which (5/6) were in the LZ group in TCIRG1 , COL1A2 , SEC24D , LRP4 , and ANO5 genes, while only one, in the LMNA gene, was in the HZ group. According to the ClinVar database, the COL1A2 variant, causative of a recessive form of osteogenesis imperfecta, is described as pathogenic, while the other variants are considered of uncertain significance (VUS). Conclusion The variant identified in COL1A2 in a woman from the LZ group highlights the genetic overlap between monogenic diseases such as osteogenesis imperfecta and complex diseases like osteoporosis. However, the other variants were not clearly associated with the extreme BMD, suggesting that there is little contribution of rare variants to postmenopausal osteoporosis.

Genetic variations in the COL1A1 and COL1A2 genes have been linked to bone mineral density (BMD) and metabolic disorders. This study analyzed the associations of COL1A1 (rs1107946, rs1800012) and COL1A2 (rs42524) polymorphisms with BMD, obesity, and type 2 diabetes (T2D) in 554 postmenopausal women. Dual-energy X-ray absorptiometry assessed BMD, and genotyping was performed alongside an evaluation of metabolic and lifestyle factors. The COL1A1 rs1107946 AA genotype was associated with higher femoral neck BMD (p < 0.05), an over 10-fold increased obesity prevalence (p = 0.038), and a 3.5-fold higher T2D risk (p = 0.011)—a novel finding. The rs1800012 polymorphism showed age-dependent BMD effects: A allele carriers had lower femoral neck BMD in the 60–69 age group but higher total hip BMD in the 70–79 age group. Additionally, COL1A2 rs42524 GG homozygotes had a significantly higher incidence of maternal fractures (p < 0.05). These results highlight COL1A1 rs1107946 as a potential marker for both skeletal and metabolic risk, demonstrate the age-specific effects of rs1800012 on BMD, and identify rs42524 as a possible genetic indicator of familial fracture risk. These insights may inform personalized approaches to osteoporosis and metabolic disease prevention.

Cannabidiol (CBD) has been suggested as a potential therapy for inflammatory and fibrotic diseases. Cannabidiol was demonstrated to reduce alcohol-induced liver inflammation and steatosis but its specific activity on the fibrotic process was not investigated. Herein, the antifibrotic effects of cannabidiol in the skin were analysed in vitro using NIH-3T3 fibroblasts and human dermal fibroblasts and in vivo using the bleomycin-induced model of skin fibrosis. In a second model, non-alcoholic liver fibrosis was induced in mice by CCl 4 exposure. Cannabidiol was administered daily, intraperitoneally in mice challenged with bleomycin and orally in CCl 4 mice, and skin and liver fibrosis and inflammation were assessed by immunochemistry. Cannabidiol inhibited collagen gene transcription and synthesis and prevented TGFβ-and IL-4 induced fibroblast migration. In the bleomycin model, cannabidiol prevented skin fibrosis and collagen accumulation around skin blood vessels, and in the CCl 4 model cannabidiol significantly attenuated liver fibrosis measured by picrosirius red and Tenascin C staining and reduced T cell and macrophage infiltration. Altogether, our data further support the rationale of the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the management of fibrotic diseases including Systemic Sclerosis and Non-Alcoholic Fatty Liver Disease.

Background LncRNA was known to be closely associated with the progression of human tumors. The role of lncRNA LIFR-AS1 in the pathogenesis and progression of gastric tumor is still unclear. The aim of this study was to investigate the function of LIFR-AS1 and the underlying mechanism in the pathogenesis and progression of gastric cancer. Methods QRT-PCR was used to evaluate the expression of LIFR-AS1, miR-29a-3p and COL1A2 in gastric tumor tissues and cells. Western blotting was used to evaluate the protein expression of COL1A2 in gastric tumor cells. CCK-8 assay, transwell assay and flow cytometry were used to evaluate the roles of LIFR-AS1, miR-29a-3p and COL1A2 in cell proliferation, invasion, migration and apoptosis. The relationship among LIFR-AS1, miR-29a-3p and COL1A2 was assessed by bioinformatics analyses and luciferase reporter assay. Results The expression levels of LIFR-AS1 were significantly increased in gastric tumor tissues and cells, while the expression levels of miR-29a-3p were decreased. The expression of miR-29a-3p was negatively correlated with the expression of LIFR-AS1 in gastric cancer tumor tissues. Knocking down of LIFR-AS1 inhibited proliferation, invasion and migration of gastric tumor cells, and induced apoptosis of gastric tumor cells. Bioinformatics analyses and integrated experiments revealed that LIFR-AS1 elevated the expression of COL1A2 through sponging miR-29a-3p, which further resulted in the progression of gastric tumor. Conclusion LIFR-AS1 plays an important role as a competing endogenous RNA in gastric tumor pathogenesis and may be a potential target for the diagnosis and treatment of gastric tumor.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a rare benign surface-based bone lesion that primarily occurs in the hands and feet of young and early middle-aged adults. The lesion presents as a firm, usually painless mass of variable duration. Radiographs reveal a well-defined, pedunculated or sessile mass arising from the cortical surface of bone without altering the architecture of the underlying cortex. On magnetic resonance imaging, BPOP shows low to intermediate signal intensity on T1-weighted images and variable signal intensity on T2-weighted images. Marked enhancement is often seen after intravenous contrast administration. Histologically, the lesion is composed of an admixture of cartilage, bone and fibrous tissue. Between the cartilage and bone is a characteristic basophilic stroma, so called \"blue bone\". Immunohistochemistry does not play a significant role in the diagnosis of BPOP. Cytogenetic studies have demonstrated recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23), inv(7)(q21.2-22q31.3-32) and inv(6)(p25q15). Most recently, gene rearrangements of collagen type I alpha 1 chain ( ) or collagen type I alpha 2 chain ( ) have been identified in a significant subset of cases. Surgical resection is the treatment of choice for symptomatic BPOP, but its local recurrence rate is relatively high. This review provides an updated overview of the clinicopathological, radiological, cytogenetic and molecular genetic features of BPOP and discusses the differential diagnosis of this uncommon lesion.

The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition. Compound heterozygotes were generated to test whether gene dosage was responsible for the less-severe phenotype of oim heterozygotes, after allelic discrimination showed that the oim mutant allele was not downregulated in heterozygotes. Compound heterozygotes had impaired bone structural properties compared to those of oim heterozygotes, albeit to a lesser extent than those of oim homozygotes. Hence, the presence of heterotrimeric type I collagen in oim heterozygotes alleviates the effect of the oim mutant allele, but a genetic interaction between homotrimeric type I collagen and the oim mutant allele leads to bone fragility.