Seno-suppressive molecules as new therapeutic perspectives in rheumatic diseases

Tachikart, Yassin; Malaise, Olivier; Mumme, Marcus; Jørgensen, Christian; Brondello, Jean-Marc

doi:10.1016/j.bcp.2019.03.017

Cited by 10 publications

(8 citation statements)

References 82 publications

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“…The presence of p16 INK4a -positive senescent cells is a well-recognized hallmark of several age-related pathologies but also ongoing tissue repair processes (for review [35, 36]). Indeed, following intrinsic and extrinsic insults, numerous tissues express senescent-induced cell cycle inhibitors such as p16 INK4a , together with the establishment of a specific micro-environment which is normally required for tissue repair coordination [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

Malaise

Tachikart

Constantinides

et al. 2019

Aging

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Tissue accumulation of p16INK4a-positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic Cdkn2a+/luc and Cdkn2aluc/luc mice, we found that the senescence-driving p16INK4a is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration. We test whether by becoming senescent, the mesenchymal stromal/stem cells (MSCs), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an in vitro p16INK4a-positive senescence model on human MSCs. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent MSC show also a seno-suppressive properties impairment favoring tissue degeneration. To evaluate in vivo the effects of p16INK4a-senescent MSC on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. MSCs isolated from these mice expressed p16INK4a. Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived MSCs was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16INK4a-positive MSCs contribute to joint alteration.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

Malaise

Tachikart

Constantinides

et al. 2019

Aging

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“…Thus, induction of senescence in FLS could have some therapeutic benefits in RA by blocking their proliferation and also by facilitating tissue clearance and repair by the immune system. However, some evidence suggests that senescence could contribute to RA progression by playing a negative role, as recently demonstrated in OA development [68,69]. Surprisingly, FLS, of which sub-groups need to be identified, harbor some features of senescent cells in response to RA chronic inflammation [66].…”

Section: Linking Senescence Onset and Synovitismentioning

confidence: 99%

“…All these findings suggest that it is important to thoroughly investigate senescence in FLS sub-types and CD4 + T cells in order to determine the consequence of their depletion in dedicated pre-clinical RA models. Indeed, senescent cell elimination with seno-suppressive drugs or by pharmaco-genetic tools has recently been used with great success in other chronic degenerative diseases (for review see [66,69]). Such future studies could lead to the development of innovative long-term therapies also for patients with RA [69].…”

Section: Linking Senescence Onset and Synovitismentioning

confidence: 99%

Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis?

Brondello

Djouad

2019

Cells

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The synovium exercises its main function in joint homeostasis through the secretion of factors (such as lubricin and hyaluronic acid) that are critical for the joint lubrication and function. The main synovium cell components are fibroblast-like synoviocytes, mesenchymal stromal/stem cells and macrophage-like synovial cells. In the synovium, cells of mesenchymal origin modulate local inflammation and fibrosis, and interact with different fibroblast subtypes and with resident macrophages. In pathologic conditions, such as rheumatoid arthritis, fibroblast-like synoviocytes proliferate abnormally, recruit mesenchymal stem cells from subchondral bone marrow, and influence immune cell activity through epigenetic and metabolic adaptations. The resulting synovial hyperplasia leads to secondary cartilage destruction, joint swelling, and pain. In the present review, we summarize recent findings on the molecular signature and the roles of stromal cells during synovial pannus formation and rheumatoid arthritis progression.

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“…Osteoarthritis (OA) is a consequence of the accumulation of age-induced damage in the joint, leading not only to cartilage degeneration, osteophytosis, or sub-chondral bone remodeling but also synovial hypertrophy or joint effusion. Progress has been made on physiopathology and OA is now considered to be a senescence-linked disease [1][2][3]. Cellular senescence is characterized by a robust cell cycle arrest with changes in cellular morphology and the expression of metabolic enzymatic activities, such as acidic senescence-associated β-galactosidase [4].…”

Section: Introductionmentioning

confidence: 99%

Influence of Glucocorticoids on Cellular Senescence Hallmarks in Osteoarthritic Fibroblast-like Synoviocytes

Malaise

Paulissen

Deroyer

et al. 2021

JCM

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Osteoarthritis (OA) is recognized as being a cellular senescence-linked disease. Intra-articular injections of glucocorticoids (GC) are frequently used in knee OA to treat synovial effusion but face controversies about toxicity. We investigated the influence of GC on cellular senescence hallmarks and senescence induction in fibroblast-like synoviocytes (FLS) from OA patients and mesenchymal stem cells (MSC). Methods: Cellular senescence was assessed via the proliferation rate, β-galactosidase staining, DNA damage and CKI expression (p21, p16INK4A). Experimental senescence was induced by irradiation. Results: The GC prednisolone did not induce an apparent senescence phenotype in FLS, with even higher proliferation, no accumulation of β-galactosidase-positive cells nor DNA damage and reduction in p21mRNA, only showing the enhancement of p16INK4A. Prednisolone did not modify experimental senescence induction in FLS, with no modulation of any senescence parameters. Moreover, prednisolone did not induce a senescence phenotype in MSC: despite high β-galactosidase-positive cells, no reduction in proliferation, no DNA damage and no CKI enhancement was observed. Conclusions: We provide reassuring in vitro data about the use of GC regarding cellular senescence involvement in OA: the GC prednisolone did not induce a senescent phenotype in OA FLS (the proliferation ratio was even higher) and in MSC and did not worsen cellular senescence establishment.

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Seno-suppressive molecules as new therapeutic perspectives in rheumatic diseases

Cited by 10 publications

References 82 publications

Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis?

Influence of Glucocorticoids on Cellular Senescence Hallmarks in Osteoarthritic Fibroblast-like Synoviocytes

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