Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis

Zhang, Mingcai; Theleman, Justin L; Lygrisse, Katherine A.; Wang, Jinxi

doi:10.1159/000496688

Cited by 44 publications

(43 citation statements)

References 49 publications

(71 reference statements)

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“…Thus, the pathogenesis of OA is linked to aging through several mechanisms, including inflammation related to aging, obesity, senescence, oxidative stress, alterations in metabolism, as well as cell signaling due to epigenetic mechanisms. Importantly, chondrocyte senescence contributes to the decreased ability of chondrocytes to repair articular cartilage tissue (12)(13)(14).…”

Section: Aging In Op and Oamentioning

confidence: 99%

Telomere length and telomerase activity in osteoporosis and osteoarthritis (Review)

et al. 2019

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Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.

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Section: Aging In Op and Oamentioning

confidence: 99%

Telomere length and telomerase activity in osteoporosis and osteoarthritis (Review)

et al. 2019

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“…Since aging is a primary risk factor in OA (50), we next examined knee joints in 12 and 18 month-old control and Mig-6 over/over mice. Toluidine blue stained sections were evaluated by two blinded observers, using OARSI recommendations (48).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of mig-6 in cartilage induces an osteoarthritis-like phenotype in mice

Bellini¹,

Pest²,

Miranda-Rodrigues³

et al. 2019

Preprint

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33 34 Background: Osteoarthritis (OA) is the most common form of arthritis and characterized by 35 degeneration of articular cartilage. Mitogen-inducible gene 6 (Mig-6) has been identified as a 36 negative regulator of the Epidermal Growth Factor Receptor (EGFR). Cartilage-specific Mig-6 37 knockout (KO) mice display increased EGFR signaling, an anabolic buildup of articular cartilage 38 and formation of chondro-osseous nodules. Since our understanding of the EGFR/Mig-6 network 39 in cartilage remains incomplete, we characterized mice with cartilage-specific overexpression of 40 Mig-6 in this study. 41 Methods: Utilizing knee joints from cartilage-specific Mig-6 overexpressing (Mig-6over/over ) mice 42 (at multiple time points), we evaluated the articular cartilage using histology, 43 immunohistochemical staining and semi-quantitative OARSI scoring at multiple ages. MicroCT 44 analysis was employed to examine skeletal morphometry, body composition, and bone mineral 45 density. 46 Results: Our data show that cartilage-specific Mig-6 overexpression did not cause any major 47 developmental abnormalities in articular cartilage, although Mig-6 over/over mice have slightly 48 shorter long bones compared to the control group. Moreover, there was no significant difference 49 in bone mineral density and body composition in any of the groups. However, our results indicate 50 that Mig-6 over/over male mice show accelerated cartilage degeneration at 12 and 18 months of age. 51 Immunohistochemistry for SOX9 demonstrated that the number of positively stained cells in Mig-52 6 over/over mice decreased relative to controls. Immunostaining for MMP13 staining is increased in 53 areas of cartilage degeneration in Mig-6 over/over mice. Moreover, staining for phospho-EGFR (Tyr-54 1173) and lubricin (PRG4) was decreased in the articular cartilage of Mig-6 over/over mice. 55 Conclusion: Overexpression of Mig-6 in articular cartilage causes no major developmental 56 phenotype; however these mice develop earlier OA during aging. These data demonstrate that 57

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“…Additional age-related changes in articular cartilage include increased chondrocyte senescence [54], oxidative stress [55], and changes in the composition and structure of ECM [56]. Although the underlying molecular causes of these changes are not completely understood, it is hypothesised that aged chondrocytes respond differently to various stimuli, such as growth factors, [53,57] and demonstrate altered molecular signatures [6].…”

Section: Discussionmentioning

confidence: 99%

“…SncRNAs are a subset of epigenetic modifiers and their role in cartilage ageing has been studied increasingly in the last decade [6,31,58]. In the current study, we have used small RNA-seq to identify alterations in sncRNAs between young and old equine chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanisms through which age can affect cartilage health remain elusive, though it is believed to be a cumulative combination of many molecular pathways rather than a single aetiology. Recent advances in the field have recognised epigenetics in ageing and diseased articular cartilage as an area of growing interest [6,7]. A class of epigenetic modifications that have attracted increasing attention are small non-coding RNAs (sncRNAs).…”

Section: Introductionmentioning

confidence: 99%

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Small Non-Coding RNAome of Ageing Chondrocytes

Balaskas

Green

Haqqi

et al. 2020

IJMS

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Ageing is a leading risk factor predisposing cartilage to osteoarthritis. However, little research has been conducted on the effect of ageing on the expression of small non-coding RNAs (sncRNAs). RNA from young and old chondrocytes from macroscopically normal equine metacarpophalangeal joints was extracted and subjected to small RNA sequencing (RNA-seq). Differential expression analysis was performed in R using package DESeq2. For transfer RNA (tRNA) fragment analysis, tRNA reads were aligned to horse tRNA sequences using Bowtie2 version 2.2.5. Selected microRNA (miRNAs or miRs) and small nucleolar RNA (snoRNA) findings were validated using real-time quantitative Polymerase Chain Reaction (qRT-PCR) in an extended cohort of equine chondrocytes. tRNA fragments were further investigated in low- and high-grade OA human cartilage tissue. In total, 83 sncRNAs were differentially expressed between young and old equine chondrocytes, including miRNAs, snoRNAs, small nuclear RNAs (snRNAs), and tRNAs. qRT-PCR analysis confirmed findings. tRNA fragment analysis revealed that tRNA halves (tiRNAs), tiRNA-5035-GluCTC and tiRNA-5031-GluCTC-1 were reduced in both high grade OA human cartilage and old equine chondrocytes. For the first time, we have measured the effect of ageing on the expression of sncRNAs in equine chondrocytes. Changes were detected in a number of different sncRNA species. This study supports a role for sncRNAs in ageing cartilage and their potential involvement in age-related cartilage diseases.

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Epigenetic Mechanisms Underlying the Aging of Articular Cartilage and Osteoarthritis

Cited by 44 publications

References 49 publications

Telomere length and telomerase activity in osteoporosis and osteoarthritis (Review)

Telomere length and telomerase activity in osteoporosis and osteoarthritis (Review)

Overexpression of mig-6 in cartilage induces an osteoarthritis-like phenotype in mice

Small Non-Coding RNAome of Ageing Chondrocytes

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