Dataset Information

Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis.

ABSTRACT: Background:Discoidin domain receptor 2 (Ddr2) is a rate-limiting factor in articular cartilage degeneration, a condition which normally leads to joint destruction. In human osteoarthritic tissues and mouse models of osteoarthritis (OA), the expression of Ddr2 increases and interacts with collagen type II, inducing the expression of matrix metalloproteinase 13 (MMP-13) and the receptor itself in chondrocytes. Moreover, conditional deletion of Ddr2 can significantly delay the progression of articular cartilage degeneration in post-traumatic OA mouse models. However, the biological effect of the conditional removal of Ddr2 in aging-related OA is still unknown. Therefore, this investigation was to determine whether the conditional removal of Ddr2 in articular cartilage could delay the cartilage degeneration in an aging-related mouse model (Col11a1+/- ) of OA. Methods:Mice Acan+/CreERT2 were bred with Ddr2flox/flox mice to generate Acan+/CreERT2;Ddr2+/flox mice. Acan+/CreERT2;Ddr2+/flox mice were crossed with Ddr2flox/flox mice to produce Acan+/CreERT2;Ddr2flox/flox mice. A similar breeding procedure was used to generate Col11a1+/-;Ddr2flox/flox mice, in which Acan+/CreERT2 mice were replaced by Col11a1+/- mice. Acan+/CreERT2;Ddr2flox/flox mice were bred with Col11a1+/-;Ddr2flox/flox mice to produce Acan+/CreERT2;Ddr2flox/flox;Col11a1+/- mice that were then treated with tamoxifen or oil at the age of 10 weeks. Knee joints from oil- and tamoxifen-treated Acan+/CreERT2;Ddr2flox/flox;Col11a1+/- mice, and Acan+/CreERT2;Ddr2flox/flox mice at the ages of 3, 9 and 15 months were collected for histology and immunohistochemistry analyses. The protein expressions of Ddr2 and Mmp-13 and the degraded collagen type II were examined. Results:The cartilage degeneration was significantly delayed in tamoxifen-treated Acan+/CreERT2;Ddr2flox/flox;Col11a1+/- mice. The scores, representing the severity of the cartilage damage, between oil- and tamoxifen-treated mice were: (mean ± SD) 1.33±0.47 vs. 1.29±0.45 (P>0.05) at the age of 3 months, 3.50±0.50 vs. 2.14±0.35 (P<0.001) at the age of 9 months, and 5.33±0.47 vs. 2.71±0.55 (P<0.001) at the age of 15 months. The protein expressions of Ddr2, Mmp-13 and the degraded collagen type II were significantly decreased in tamoxifen-treated mice. Conclusions:The removal of Ddr2 could significantly attenuate the cartilage degeneration in Col11a1+/- mice.

SUBMITTER: Li X

PROVIDER: S-EPMC7576030 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis.

Li Xiaolong X Chen Yi Y Xu Rui R Wang Yan Y Jian Fan F Long Hu H Lai Wenli W

Annals of translational medicine 20200901 18

<h4>Background</h4>Discoidin domain receptor 2 (<i>Ddr2</i>) is a rate-limiting factor in articular cartilage degeneration, a condition which normally leads to joint destruction. In human osteoarthritic tissues and mouse models of osteoarthritis (OA), the expression of <i>Ddr2</i> increases and interacts with collagen type II, inducing the expression of matrix metalloproteinase 13 (MMP-13) and the receptor itself in chondrocytes. Moreover, conditional deletion of Ddr2 can significantly delay the ...[more]

PMID: 33241027

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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.

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.

Dataset Information

Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis.

Publications

Delay in articular cartilage degeneration of the knee joint by the conditional removal of discoidin domain receptor 2 in a spontaneous mouse model of osteoarthritis.

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