9 research outputs found
Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth
Copyright: © 2015 Kung et al. Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2á and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole
Comprehensive Expression Analysis of microRNAs and mRNAs in Synovial Tissue from a Mouse Model of Early Post-Traumatic Osteoarthritis
To better understand the molecular processes involved in driving osteoarthritis disease progression we characterized expression profiles of microRNAs (miRNA) and mRNAs in synovial tissue from a post-traumatic OA mouse model. OA was induced in 10-12 week old male C57BL6 mice by bilateral surgical destabilization of the medial meniscus (DMM). RNA isolated from the anterior synovium of mice at 1 and 6 weeks post-surgery was subject to expression profiling using Agilent microarrays and qPCR. OA severity was determined histologically. Anterior and posterior synovitis decreased with post-operative time after sham and DMM. No differences in synovitis parameters were evident between sham and DMM in the anterior synovium at either time. While expression profiling revealed 394 miRNAs were dysregulated between 1 and 6 week time-points in the anterior synovium, there were no significant changes in miRNA or mRNA expression between DMM and sham mice at both time-points. Bioinformatic analysis of the miRNAs and mRNAs differentially expressed in tandem with the resolution of anterior synovial inflammation revealed similar biological processes and functions, including organismal injury, connective tissue disorder and inflammatory responses. Our data demonstrates that early OA-specific patterns of synovial miRNAs or mRNAs dysregulation could not be identified in this model of post-traumatic OA
Increased Classical Endoplasmic Reticulum Stress Is Sufficient to Reduce Chondrocyte Proliferation Rate in the Growth Plate and Decrease Bone Growth
Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease
OBJECTIVE: To identify candidate microRNAs (miRNAs) that potentially regulate the initiation and progression of osteoarthritis (OA). METHODS: OA was induced in 10-12-week-old male wild-type C57BL/6 mice and in mice resistant to aggrecanase cleavage (Acan p.374ALGS→374NVYS) by destabilization of the medial meniscus (DMM). Pathologic changes of OA were scored histologically. RNA from cartilage and subchondral bone was harvested in parallel by laser microdissection at 1 week and 6 weeks postsurgery. Global miRNA expression profiling was performed using Agilent microarrays and was validated by quantitative polymerase chain reaction analysis. RESULTS: Wild-type DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis, and osteophyte formation. While no miRNA dysregulation was seen in subchondral bone, 139 miRNAs were differentially expressed in cartilage obtained at 1 and/or 6 weeks after OA initiation from wild-type mice that underwent DMM. To prioritize OA candidates, dysregulated miRNAs with human orthologs were filtered, and paired miRNA/messenger RNA (mRNA) expression analysis was conducted to identify those with corresponding changes in mRNA target transcripts in the DMM mouse cartilage. An important cohort also overlapped with miRNAs identified in human end-stage OA. Comparisons of miRNA dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically ablated demonstrated that all candidates were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Furthermore, functional enrichment analysis and data annotation revealed the responses to mechanical stimuli, apoptotic processes, and core extracellular matrix structural and regulatory factors to be potentially influenced by OA-dysregulated miRNA/mRNA networks. CONCLUSION: Our comprehensive analyses identified high-priority miRNA candidates that have potential as biomarkers and therapeutic targets in human OA