Microarray study of gene expression profile to identify new candidate genes involved in the molecular mechanism of leptin-induced knee joint osteoarthritis in rat.
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ABSTRACT:
SUBMITTER: Fan Q
PROVIDER: S-EPMC5496599 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Microarray study of gene expression profile to identify new candidate genes involved in the molecular mechanism of leptin-induced knee joint osteoarthritis in rat.
Fan Qing Q Liu Zhu Z Shen Chao C Li Hai H Ding Jing J Jin Fangchun F Sha Lin L Zhang Ziming Z
Hereditas 20170704
<h4>Background</h4>Osteoarthritis (OA) is one of the most prevalent chronic joint diseases while the precise genetic mechanism remains elusive. In this study, we investigated the gene expression profile in OA by microarray analysis.<h4>Results</h4>Histopathological characteristics of OA cartilage were examined using a rat model of leptin-induced OA. Gene expression profile of leptin-induced articular cartilage and healthy rat cartilage were compared using genome-wide microarray hybridization. A ...[more]
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Project description:Our objective was to determine the efficacy and feasibility of a new approach for identifying candidate biomarkers for knee osteoarthritis (OA), based on selecting promising candidates from a range of high-frequency acoustic emission (AE) measurements generated during weight-bearing knee movement. Candidate AE biomarkers identified by this approach could then be validated in larger studies for use in future clinical trials and stratified medicine applications for this common health condition. A population cohort of participants with knee pain and a Kellgren-Lawrence (KL) score between 1-4 were recruited from local NHS primary and secondary care sites. Focusing on participants' self-identified worse knee, and using our established movement protocol, sources of variation in AE measurement and associations of AE markers with other markers were explored. Using this approach we identified 4 initial candidate AE biomarkers, of which "number of hits" showed the best reproducibility, in terms of within-session, day to day, week to week, between-practitioner, and between-machine variation, at 2 different machine upper frequency settings. "Number of hits" was higher in knees with KL scores of 2 than in KL1, and also showed significant associations with pain in the contralateral knee, and with body weight. "Hits" occurred predominantly in 2 of 4 defined movement quadrants. The protocol was feasible and acceptable to all participants and professionals involved. This study demonstrates how AE measurement during simple sit-stand-sit movements can be used to generate novel candidate knee OA biomarkers. AE measurements probably reflect a composite of structural changes and joint loading factors. Refinement of the method and increasing understanding of factors contributing to AE will enable this approach to be used to generate further candidate biomarkers for validation and potential use in clinical trials.
| S-EPMC6795455 | biostudies-literature
Project description:Osteoarthritis (OA) is the most prevalent chronic joint disease and the precise genetic mechanisms are yet to be fully elucidated. The aim of this study is to evaluate, for the first time, the differences in gene expression profiles of healthy and leptin-induced cartilage in rat. To investigate the underlying pathogenic factors in OA, alterations in gene expression between leptin-induced articular cartilage rat models and healthy control rat models were investigated using the Whole Rat Genome Oligo Microarray. In the present study, 1857 differentially expressed genes (DEGs; 1197 up-regulated and 660 down-regulated) were identified. Expression of some OA-related known genes is known to be associated with leptin induction, including matrix metalloproteinase (MMP), inflammatory factors, growth factors and genes involved in cell death, apoptosis and osteoclast differentiation. However, some new candidate genes that had never been reported to be related with OA, such as BCL2L11, were consistently observed to be up-regulated, suggesting they might be involved in OA progression. Our findings indicate that leptin plays an important role in the progression of OA by mediating expression change in multiple genes, although the molecular mechanisms need to be further clarified. Further study of these leptin-induced genes may provide new insights into understanding the molecular mechanisms underlying OA.
2016-08-19 | GSE85785 | GEO
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2016-08-19 | E-GEOD-85785 | biostudies-arrayexpress
Project description:ObjectiveTo compare C-reactive protein (CRP) and matrix metalloproteinase-generated neoepitope of CRP (CRPM) as biomarkers of inflammation and radiographic severity in patients with knee osteoarthritis.MethodsParticipants with symptomatic osteoarthritis (n=25) of at least one knee underwent knee radiographic imaging and radionuclide etarfolatide imaging to quantify inflammation of the knees and other appendicular joints. For purposes of statistical analysis, semi-quantitative etarfolatide and radiographic imaging scores were summed across the knees; etarfolatide scores were also summed across all joints to provide a multi-joint synovitis measure. Multiple inflammation and collagen-related biomarkers were measured by ELISA including CRP, CRPM, MMP-generated neoepitopes of type I collagen and type III collagen in serum (n=25), and CD163 in serum (n=25) and synovial fluid (n=18).ResultsBMI was associated with CRP (p=0.001), but not CRPM (p=0.753). Adjusting for BMI, CRP was associated with radiographic knee osteophyte score (p=0.002), while CRPM was associated with synovitis of the knee (p=0.017), synovitis of multiple joints (p=0.008), and macrophage marker CD163 in serum (p=0.009) and synovial fluid (p=0.03). CRP correlated with MMP-generated neoepitope of type I collagen in serum (p=0.045), and CRPM correlated with MMP-generated neoepitope of type III collagen in serum (p<0.0001). No biomarkers correlated with age, knee pain, or WOMAC pain.ConclusionsTo our knowledge, this is the first time that CRPM has been shown to be associated with knee and multi-joint inflammation based on objective imaging (etarfolatide) and biomarker (CD163) measures. These results demonstrate the capability of biomarker measurements to reflect complex biological processes and for neoepitope markers to more distinctly reflect acute processes than their precursor proteins. CRPM is a promising biomarker of local and systemic inflammation in knee OA that is associated with cartilage degradation and is independent of BMI. CRPM is a potential molecular biomarker alternative to etarfolatide imaging for quantitative assessment of joint inflammation.
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Project description:OBJECTIVE: To analyze genome-wide changes in chondrocyte gene expression in a surgically induced model of early osteoarthritis (OA) in rats, to assess the similarity of this model to human OA, and to identify genes and mechanisms leading to OA pathogenesis. METHODS: OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression. Expression patterns of selected dysregulated genes, including Col2a1, Mmp13, Adamts5, Ctsc, Ptges, and Cxcr4, were validated by real-time polymerase chain reaction, immunofluorescence, or immunohistochemistry 2, 4, and 8 weeks after surgery. RESULTS: After normalization, comparison of OA and sham-operated samples showed 1,619 differentially expressed probe sets with changes in their levels of expression >/=1.5-fold, 722 with changes >/=2-fold, 135 with changes >/=4-fold, and 20 with changes of 8-fold. Dysregulated genes known to be involved in human OA included Mmp13, Adamts5, and Ptgs2, among others. Several dysregulated genes (e.g., Reln, Phex, and Ltbp2) had been identified in our earlier microarray study of hypertrophic chondrocyte differentiation. Other genes involved in cytokine and chemokine signaling, including Cxcr4 and Ccl2, were identified. Changes in gene expression were also observed in the contralateral knee, validating the sham operation as the appropriate control. CONCLUSION: Our results demonstrate that the animal model mimics gene expression changes seen in human OA, supporting the relevance of newly identified genes and pathways to early human OA. We propose new avenues for OA pathogenesis research and potential targets for novel OA treatments, including cathepsins and cytokine, chemokine, and growth factor signaling pathways, in addition to factors controlling the progression of chondrocyte differentiation. Experiment Overall Design: OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees, 28 days post-surgery. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression.
2009-04-23 | E-GEOD-8077 | biostudies-arrayexpress
Project description:OBJECTIVE:Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. METHOD:20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS4) was collected at baseline, 3, 6 and 12 months. RESULTS:13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ?2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGF?-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS4 over 6 months showed greater increases in FGF-2 and TGF?-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS4 over 12 months. CONCLUSION:Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.
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Project description:Increased walking knee joint stiffness has been reported in patients with knee osteoarthritis (OA) as a compensatory strategy to improve knee joint stability. However, presence of episodic self-reported knee instability in a large subgroup of patients with knee OA may be a sign of inadequate walking knee joint stiffness. The objective of this work was to evaluate the differences in walking knee joint stiffness in patients with knee OA with and without self-reported instability and examine the relationship between walking knee joint stiffness with quadriceps strength, knee joint laxity, and varus knee malalignment. Overground biomechanical data at a self-selected gait velocity was collected for 35 individuals with knee OA without self-reported instability (stable group) and 17 individuals with knee OA and episodic self-reported instability (unstable group). Knee joint stiffness was calculated during the weight-acceptance phase of gait as the change in the external knee joint moment divided by the change in the knee flexion angle. The unstable group walked with lower knee joint stiffness (p=0.01), mainly due to smaller heel-contact knee flexion angles (p<0.01) and greater knee flexion excursions (p<0.01) compared to their knee stable counterparts. No significant relationships were observed between walking knee joint stiffness and quadriceps strength, knee joint laxity or varus knee malalignment. Reduced walking knee joint stiffness appears to be associated with episodic knee instability and independent of quadriceps muscle weakness, knee joint laxity or varus malalignment. Further investigations of the temporal relationship between self-reported knee joint instability and walking knee joint stiffness are warranted.
| S-EPMC5572142 | biostudies-other
Project description:Objectives:The aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA). Methods:The expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo. Results:In total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1?-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues. Conclusion:This study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients.Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:288-301. DOI: 10.1302/2046-3758.86.BJR-2018-0297.R1.
| S-EPMC6609867 | biostudies-literature
Project description:ObjectivesThe aim of this study was to provide a comprehensive understanding of alterations in messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) in cartilage affected by osteoarthritis (OA).MethodsThe expression profiles of mRNAs, lncRNAs, and circRNAs in OA cartilage were assessed using whole-transcriptome sequencing. Bioinformatics analyses included prediction and reannotation of novel lncRNAs and circRNAs, their classification, and their placement into subgroups. Gene ontology and pathway analysis were performed to identify differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and differentially expressed circRNAs (DECs). We focused on the overlap of DEGs and targets of DELs previously identified in seven high-throughput studies. The top ten DELs were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in articular chondrocytes, both in vitro and in vivo.ResultsIn total, 739 mRNAs, 1152 lncRNAs, and 42 circRNAs were found to be differentially expressed in OA cartilage tissue. Among these, we identified 18 overlapping DEGs and targets of DELs, and the top ten DELs were screened by expression profile analysis as candidate OA-related genes. WISP2, ATF3, and CHI3L1 were significantly increased in both normal versus OA tissues and normal versus interleukin (IL)-1β-induced OA-like cell models, while ADAM12, PRELP, and ASPN were shown to be significantly decreased. Among the identified DELs, we observed higher expression of ENST00000453554 and MSTRG.99593.3, and lower expression of MSTRG.44186.2 and NONHSAT186094.1 in normal versus OA cells and tissues.ConclusionThis study revealed expression patterns of coding and noncoding RNAs in OA cartilage, which added sets of genes and noncoding RNAs to the list of candidate diagnostic biomarkers and therapeutic agents for OA patients.Cite this article: H. Li, H. H. Yang, Z. G. Sun, H. B. Tang, J. K. Min. Whole-transcriptome sequencing of knee joint cartilage from osteoarthritis patients. Bone Joint Res 2019;8:290-303. DOI: 10.1302/2046-3758.87.BJR-2018-0297.R1.
| S-EPMC6691371 | biostudies-literature