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Cell-type-specific gene expression patterns in the knee cartilage in an osteoarthritis rat model.

ABSTRACT: Osteoarthritis (OA) is a chronic degenerative disease that leads to joint failure, pain, and disability. Gene regulation is implicated as a driver of the imbalance between the expression of catabolic and anabolic factors that eventually leads to the degeneration of osteoarthritic cartilage. In our model, knee-joint OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate (MIA) injections. Whole-genome microarrays were used to analyse the alterations in gene expression during the time-course of OA development (at 2, 14, and 28 days post-injection) in rat knee joints. The identified co-expressed groups of genes were analysed for enriched regulatory mechanisms, functional classes, and cell-type-specific expression. This analysis revealed 272 regulated transcripts (ANOVA FDR < 0.1% and fold > 2). Functionally, the five major gene expression patterns (A-E) were connected to PPAR signalling and adipogenesis (in cluster A), WNT signalling (in cluster B), endochondral ossification (in cluster C), matrix metalloproteinases and the ACE/RAGE pathway (in cluster D), and the Toll-like receptor, and IL-1 signalling pathways (in cluster E). Moreover, the dynamic profiles of these transcriptional changes were assigned to cellular compartments of the knee joint. Classifying the molecular processes associated with the development of cartilage degeneration provides novel insight into the OA disease process. Our study identified groups of co-regulated genes that share functional relationships and that may play an important role in the early and intermediate stages of OA.

SUBMITTER: Korostynski M

PROVIDER: S-EPMC5748428 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Cell-type-specific gene expression patterns in the knee cartilage in an osteoarthritis rat model.

Korostynski Michal M Malek Natalia N Piechota Marcin M Starowicz Katarzyna K

Functional & integrative genomics 20171113 1

Osteoarthritis (OA) is a chronic degenerative disease that leads to joint failure, pain, and disability. Gene regulation is implicated as a driver of the imbalance between the expression of catabolic and anabolic factors that eventually leads to the degeneration of osteoarthritic cartilage. In our model, knee-joint OA was induced in male Wistar rats by intra-articular sodium monoiodoacetate (MIA) injections. Whole-genome microarrays were used to analyse the alterations in gene expression during ...[more]

PMID: 29134405

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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.

Project description:BackgroundJoint hemorrhage is caused by trauma, ligament reconstruction surgery, and bleeding disorders such as hemophilia. Recurrence of hemorrhage in the joint space induces hemosiderotic synovitis and oxidative stress, resulting in both articular cartilage degeneration and arthropathy. Joint immobilization is a common treatment option for articular fractures accompanied by joint hemorrhage. Although joint hemorrhage has negative effects on the articular cartilage, there is no consensus on whether a reduction in joint hemorrhage would effectively prevent articular cartilage degeneration. The purpose of this study was to investigate the effect of joint hemorrhage combined with joint immobilization on articular cartilage degeneration in a rat immobilized knee model.MethodsThe knee joints of adult male rats were immobilized at the flexion using an internal fixator from 3 days to 8 weeks. The rats were randomly divided into the following groups: immobilized blood injection (Im-B) and immobilized-normal saline injection (Im-NS) groups. The cartilage was evaluated in two areas (contact and non-contact areas). The cartilage was used to assess chondrocyte count, Modified Mankin score, and cartilage thickness. The total RNA was extracted from the cartilage in both areas, and the expression of metalloproteinase (MMP)-8, MMP-13, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α was measured by quantitative real-time polymerase chain reaction.ResultsThe number of chondrocytes in the Im-B group significantly decreased in both areas, compared with that in the Im-NS group. Modified Mankin score from 4 to 8 weeks of the Im-B group was significantly higher than that of the Im-NS group only in the contact area. The expression of MMP-8 and MMP-13 from 2 to 4 weeks and TNF-α from 2 to 8 weeks significantly increased in the Im-B group compared with those in the Im-NS group, but there was no significant difference in IL-1β expression.ConclusionsThe results showed that joint hemorrhage exacerbated immobilization-induced articular cartilage degeneration. Drainage of a joint hemorrhage or avoidance of loading may help prevent cartilage degeneration during joint immobilization with a hemorrhage.

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Cell-type-specific gene expression patterns in the knee cartilage in an osteoarthritis rat model.

Publications

Cell-type-specific gene expression patterns in the knee cartilage in an osteoarthritis rat model.

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