Cellular senescence in osteoarthritis and anti-aging strategies

Hou, Angyang; Chen, Peng; Tang, He; Meng, Hui; Cheng, Xiaoqing; Wang, Yu; Zhang, Yuming; Peng, Jiang

doi:10.1016/j.mad.2018.08.002

Cited by 39 publications

(29 citation statements)

References 69 publications

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“…The BrdU cell proliferation assay showed a 50% reduction of cell proliferation in SfMSCs isolated from 40-year-old horses compared to 3Y donors, suggesting the acquisition of a gradual senescent phenotype, one of the most repetitive hallmarks of aging [38,44]. These results are confirmed by a doubling time assay, which showed the highest time for cell doubling in the 40Y sample.…”

Section: Discussionmentioning

confidence: 75%

“…Osteoarthritis is a degenerative disease that strongly correlates with age [38,39]. Mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit a superior chondrogenic ability compared with those derived from non-joint tissues [1,40,41]; thus, they represent the best choice for the regeneration and repair of cartilage [40].…”

Section: Discussionmentioning

confidence: 99%

“…All in all, our data demonstrate the lack of a relationship between the expression of mesenchymal stem cells and multipotency markers with aging, and the ability to isolate adult stem cells even from healthy aged donors. Although previous studies on age-related alterations of stem cells demonstrated stem cell exhaustion as a hallmark of aging [44], this is not present in hematopoietic stem cells, which show an increase in stem cell proliferation related to aging [38].…”

Section: Discussionmentioning

confidence: 99%

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Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model

Mazzotti

Teti

Falconi

et al. 2019

Cells

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Osteoarthritis is a degenerative disease that strongly correlates with age and promotes the breakdown of joint cartilage and subchondral bone. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stromal cells (MSCs) isolated from adult tissues. It seems that MSCs derived from synovial joint tissues exhibit superior chondrogenic ability, but their unclear distribution and low frequency actually limit their clinical application. To date, the influence of aging on synovial joint derived MSCs’ biological characteristics and differentiation abilities remains unknown, and a full understanding of the mechanisms involved in cellular aging is lacking. The aim of this study was therefore to investigate the presence of age-related alterations in synovial fluid MSCs and their influence on the potential ability of MSCs to differentiate toward chondrogenic phenotypes. Synovial fluid MSCs, isolated from healthy equine donors from 3 to 40 years old, were cultured in vitro and stimulated towards chondrogenic differentiation for up to 21 days. An equine model was chosen due to the high degree of similarity of the anatomy of the knee joint to the human knee joint and as spontaneous disorders develop that are clinically relevant to similar human disorders. The results showed a reduction in cell proliferation correlated with age and the presence of age-related tetraploid cells. Ultrastructural analysis demonstrated the presence of morphological features correlated with aging such as endoplasmic reticulum stress, autophagy, and mitophagy. Alcian blue assay and real-time PCR data showed a reduction of efficiency in the chondrogenic differentiation of aged synovial fluid MSCs compared to young MSCs. All these data highlighted the influence of aging on MSCs’ characteristics and ability to differentiate towards chondrogenic differentiation and emphasize the importance of considering age-related alterations of MSCs in clinical applications.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model

Mazzotti

Teti

Falconi

et al. 2019

Cells

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“…Senescent cells, although permanently non-dividing, remain metabolically active and secrete a range of pro-inflammatory cytokines, chemokines, proteases, and growth factors, called the SASP. The SASP influences the tissue microenvironment, accelerates aging, and contributes to local and systemic dysfunction in diseases such as osteoarthritis [4,5]. Furthermore, it can, in a paracrine manner, induce senescence, which further intensifies tissue deterioration [6].…”

Section: Introductionmentioning

confidence: 99%

Curcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro

Cherif

Bisson

Jarzem

et al. 2019

JCM

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Curcumin and o-Vanillin cleared senescent intervertebral disc (IVD) cells and reduced the senescence-associated secretory phenotype (SASP) associated with inflammation and back pain. Cells from degenerate and non-mildly-degenerate human IVD were obtained from organ donors and from patients undergoing surgery for low back pain. Gene expression of senescence and SASP markers was evaluated by RT-qPCR in isolated cells, and protein expression of senescence, proliferation, and apoptotic markers was evaluated by immunocytochemistry (ICC). The expression levels of SASP factors were evaluated by enzyme-linked immunosorbent assay (ELISA). Matrix synthesis was verified with safranin-O staining and the Dimethyl-Methylene Blue Assay for proteoglycan content. Western blotting and ICC were used to determine the molecular pathways targeted by the drugs. We found a 40% higher level of senescent cells in degenerate compared to non-mildly-degenerate discs from unrelated individuals and a 10% higher level in degenerate compared to non-mildly-degenerate discs from the same individual. Higher levels of senescence were associated with increased SASP. Both drugs cleared senescent cells, and treatment increased the number of proliferating as well as apoptotic cells in cultures from degenerate IVDs. The expression of SASP factors was decreased, and matrix synthesis increased following treatment. These effects were mediated through the Nrf2 and NFkB pathways.

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“…Although OA is not an inevitable consequence of senescence, aging is a strong risk factor for OA [ 2 ]. Chondrocytes undergo age-dependent senescence, which is characterized by a decline in the proliferative and synthetic capacity of cellular products, including their extracellular matrices; this is considered to play a significant role in the pathology of OA [ 3 ]. Although aging and OA are closely linked, they are independent processes.…”

Section: Introductionmentioning

confidence: 99%

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

Kuwahara

Kadoya

Kondo

et al. 2020

IJMS

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Aging is a major risk factor of osteoarthritis, which is characterized by the degeneration of articular cartilage. CCN3, a member of the CCN family, is expressed in cartilage and has various physiological functions during chondrocyte development, differentiation, and regeneration. Here, we examine the role of CCN3 in cartilage maintenance. During aging, the expression of Ccn3 mRNA in mouse primary chondrocytes from knee cartilage increased and showed a positive correlation with p21 and p53 mRNA. Increased accumulation of CCN3 protein was confirmed. To analyze the effects of CCN3 in vitro, either primary cultured human articular chondrocytes or rat chondrosarcoma cell line (RCS) were used. Artificial senescence induced by H2O2 caused a dose-dependent increase in Ccn3 gene and CCN3 protein expression, along with enhanced expression of p21 and p53 mRNA and proteins, as well as SA-β gal activity. Overexpression of CCN3 also enhanced p21 promoter activity via p53. Accordingly, the addition of recombinant CCN3 protein to the culture increased the expression of p21 and p53 mRNAs. We have produced cartilage-specific CCN3-overexpressing transgenic mice, and found degradative changes in knee joints within two months. Inflammatory gene expression was found even in the rib chondrocytes of three-month-old transgenic mice. Similar results were observed in human knee articular chondrocytes from patients at both mRNA and protein levels. These results indicate that CCN3 is a new senescence marker of chondrocytes, and the overexpression of CCN3 in cartilage may in part promote chondrocyte senescence, leading to the degeneration of articular cartilage through the induction of p53 and p21.

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Cellular senescence in osteoarthritis and anti-aging strategies

Cited by 39 publications

References 69 publications

Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model

Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model

Curcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro

CCN3 (NOV) Drives Degradative Changes in Aging Articular Cartilage

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