Summary
Objective
Transcriptomic changes in joint tissues during the development of osteoarthritis (OA)
are of interest for the discovery of biomarkers and mechanisms of disease. The objective
of this study was to use the rat medial meniscus transection (MMT) model to discover
stage and tissue-specific transcriptomic changes.
Design
Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium
were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed
for RNA-sequencing. Differentially expressed genes (DEG) were used to identify pathways
and mechanisms. Published transcriptomic datasets from animal models and human OA
were used to confirm and extend present findings.
Results
The total number of DEGs was already high at 2 weeks (723 in meniscus), followed by
cartilage (259) and synovium (42) and declined to varying degrees in meniscus and
synovium but increased in cartilage at 6 weeks. The most upregulated genes included
tenascins. The ‘response to mechanical stimulus’ and extracellular matrix-related
pathways were enriched in both cartilage and meniscus. Pathways that were enriched
in synovium at 4 weeks indicate processes related to synovial hyperplasia and fibrosis.
Synovium also showed upregulation of IL-11 and several MMPs. The mechanical stimulus
pathway included upregulation of the mechanoreceptors PIEZO1, PIEZO2 and TRPV4 and
nerve growth factor. Analysis of data from prior RNA-sequencing studies of animal
models and human OA support these findings.
Conclusion
These results indicate several shared pathways that are affected during OA in cartilage
and meniscus and support the role of mechanotransduction and other pathways in OA
pathogenesis.
Keywords
Abbreviations:
RNA-seq (RNA-sequencinig), DEG (Differentially Expressed Genes)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Osteoarthritis and CartilageAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis?.Curr Opin Rheumatol. 2021; 33: 74-83
- Genetics of osteoarthritis.Curr Opin Rheumatol. 2011; 23: 479-483
- Risk factors and the natural history of accelerated knee osteoarthritis: a narrative review.BMC Muscoskel Disord. 2020; : 21
- Autophagy and cartilage homeostasis mechanisms in joint health, aging and OA.Nat Rev Rheumatol. 2011; 7: 579-587
- Osteoarthritis: a disease of the joint as an organ.Arthritis Rheum. 2012; 64: 1697-1707
- Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis.Arthritis Rheum. 2011; 63: 2700-2710
- Animal models of osteoarthritis.J Musculoskelet Neuronal Interact. 2001; 1: 363-376
- Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia.Osteoarthritis Cartilage. 2006; 14: 1041-1048
- Induction of osteoarthritis in the rat by surgical tear of the meniscus: inhibition of joint damage by a matrix metalloproteinase inhibitor (vol 10, pg 785, 2002) (vol 10, pg 905, 2002).Osteoarthritis Cartilage. 2003; 11: 299
- The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat.Osteoarthritis Cartilage. 2010; 18: S24-S34
- UMI-tools: modeling sequencing errors in Unique Molecular Identifiers to improve quantification accuracy.Genome Res. 2017; 27: 491-499
- The nf-core framework for community-curated bioinformatics pipelines.Nat Biotechnol. 2020; 38: 276-278
- STAR: ultrafast universal RNA-seq aligner.Bioinformatics. 2013; 29: 15-21
- featureCounts: an efficient general purpose program for assigning sequence reads to genomic features.Bioinformatics. 2014; 30: 923-930
- Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.Genome Biol. 2014; 15
- Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.Osteoarthritis Cartilage. 2018; 26: 1531-1538
- Controlling the false discovery rate in behavior genetics research.Behav Brain Res. 2001; 125: 279-284
- Human cartilage glycoprotein 39-biomarker of joint damage in knee osteoarthritis.Int Orthop. 2009; 33: 1165-1170
- Analysis of early changes in the articular cartilage transcriptisome in the rat meniscal tear model of osteoarthritis: pathway comparisons with the rat anterior cruciate transection model and with human osteoarthritic cartilage.Osteoarthritis Cartilage. 2010; 18: 992-1000
- Quantitative histological grading methods to assess subchondral bone and synovium changes subsequent to medial meniscus transection in the rat.Connect Tissue Res. 2017; 58: 373-385
- Angiogenesis in two animal models of osteoarthritis.Osteoarthritis Cartilage. 2008; 16: 61-69
- Role of tenascin-C in articular cartilage.Mod Rheumatol. 2018; 28: 215-220
- Tenascin-C in osteoarthritis and rheumatoid arthritis.Front Immunol. 2020; : 11
- Transcriptional analysis of micro-dissected articular cartilage in post-traumatic murine osteoarthritis.Osteoarthritis Cartilage. 2015; 23: 616-628
- Latent TGF-beta activation is a hallmark of the tenascin family.Front Immunol. 2021; : 12
- Deficiency of tenascin-C attenuated cardiac injury by inactivating TLR4/NLRP3/caspase-1 pathway after myocardial infarction.Cell Signal. 2021; : 86
- TSG-6: a multifunctional protein associated with inflammation.J Cell Sci. 2003; 116: 1863-1873
- Detrimental role for human high temperature requirement serine protease A1 (HTRA1) in the pathogenesis of intervertebral disc (IVD) degeneration.J Biol Chem. 2012; 287: 21335-21345
- AEBP1 is a novel oncogene: mechanisms of action and signaling pathways.J Oncol. 2020; : 2020
- Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.J Biol Chem. 2012; 287: 39171-39181
- Protein Cytl1: its role in chondrogenesis, cartilage homeostasis, and disease.Cell Mol Life Sci. 2019; 76: 3515-3523
- Evidence for enhanced collagen type III deposition focally in the territorial matrix of osteoarthritic hip articular cartilage.Osteoarthritis Cartilage. 2016; 24: 1029-1035
- Direct assessment of articular cartilage and underlying subchondral bone reveals a progressive gene expression change in human osteoarthritic knees.Osteoarthritis Cartilage. 2013; 21: S12
- Cathepsin K: the action in and beyond bone.Front Cell Dev Biol. 2020; 8
- Cathepsin B in osteoarthritis: uncontrolled proteolysis in the wrong place.Semin Arthritis Rheum. 2005; 34: 24-28
- 75-kd sirtuin 1 blocks tumor necrosis factor a-mediated apoptosis in human osteoarthritic chondrocytes.Arthritis Rheum. 2012; 64: 718-728
- A preliminary study of combined detection of COMP, TIMP-1, and MMP-3 in synovial fluid: potential indicators of osteoarthritis progression.Cartilage. 2021; 13: 1421S-1430S
- Exploring the osteoarthritis-related genes by gene expression analysis.Eur Rev Med Pharmacol Sci. 2014; 18: 3056-3062
- Comparison of rheumatoid arthritis (RA) and osteoarthritis (OA) based on microarray profiles of human joint fibroblast-like synoviocytes.Cell Biochem Funct. 2019; 37: 31-41
- Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo.Arthritis Rheum. 2012; 64: 2278-2288
- Global analyses of gene expression in early experimental osteoarthritis.Arthritis Rheum. 2007; 56: 1854-1868
- PPAR gamma preservation via promoter demethylation alleviates osteoarthritis in mice.Ann Rheum Dis. 2019; 78: 1420-1429
- Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis.Ageing Res Rev. 2021; 67
- The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review.Osteoarthritis Cartilage. 2020; 28: 400-409
- Interaction of HIF1 alpha and beta-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice.Proc Natl Acad Sci U S A. 2016; 113: 5453-5458
- The role of inflammation in the pathogenesis of osteoarthritis.Mediat Inflamm. 2020; : 2020
- Regional gene expression analysis of multiple tissues in an experimental animal model of post-traumatic osteoarthritis.Osteoarthritis Cartilage. 2019; 27: 294-303
- Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: potential therapeutic targets for osteoarthritis.Channels. 2021; 15: 339-359
- The potential role of mechanically sensitive ion channels in the physiology, injury, and repair of articular cartilage.J Orthop Surg. 2020; 28
- Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis.Proc Natl Acad Sci U S A. 2021; : 118
- Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage.Proc Natl Acad Sci U S A. 2014; 111: E5114-E5122
- Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation.J Biol Chem. 2007; 282: 32158-32167
- Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4 age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice.Arthritis Rheum. 2010; 62: 2973-2983
- TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading.Proc Natl Acad Sci U S A. 2014; 111: 1316-1321
- CITED2 mediates the cross-talk between mechanical loading and IL-4 to promote chondroprotection.Ann N Y Acad Sci. 2019; 1442: 128-137
- Strain-induced mechanotransduction through primary cilia, extracellular ATP, purinergic calcium signaling, and ERK1/2 transactivates CITED2 and downregulates MMP-1 and MMP-13 gene expression in chondrocytes.Osteoarthritis Cartilage. 2016; 24: 892-901
- Nociceptive sensitizers are regulated in damaged joint tissues, including articular cartilage, when osteoarthritic mice display pain behavior.Arthritis Rheumatol. 2016; 68: 857-867
- Modulation of TRPV4 by diverse mechanisms.Int J Biochem Cell Biol. 2016; 78: 217-228
- Characterization of nerve growth factor-induced mechanical and thermal hypersensitivity in rats.Eur J Pain. 2013; 17: 469-479
- Piezo2 knockdown inhibits noxious mechanical stimulation and NGF-induced sensitization in A-delta bone afferent neurons.Front Physiol. 2021; 12644929
- Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis.PLoS One. 2013; 8e54633
- Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis.Sci Rep. 2020; 1010868
Article info
Publication history
Published online: October 27, 2022
Accepted:
October 3,
2022
Received:
April 20,
2022
Identification
Copyright
© 2022 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
