Mechanisms and therapeutic implications of cellular senescence in osteoarthritis

Coryell, Philip; Diekman, Brian O.; Loeser, Richard F.

doi:10.1038/s41584-020-00533-7

Cited by 310 publications

(197 citation statements)

References 123 publications

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“…The innate immune activation caused by the dysregulation of the immune system with aging is considered to play a crucial role in the chronic inflammation of OA (Jeon et al, 2018). Age-related mitochondrial dysfunction and associated oxidative stress might induce senescence in joint tissue cells (Coryell et al, 2020). The accumulation of SnCs in joints causes the secretion of proinflammatory and pro-catabolic factors (cytokines, chemokines, MMPs), which is called a "senescence-associated secretory phenotype" (SASP) (Childs et al, 2017;Millerand et al, 2019).…”

Section: Targeting Senescent Cellsmentioning

confidence: 99%

New Trends in Pharmacological Treatments for Osteoarthritis

et al. 2021

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Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

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Section: Targeting Senescent Cellsmentioning

confidence: 99%

New Trends in Pharmacological Treatments for Osteoarthritis

et al. 2021

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“…55 The increased chondrocyte senescence correlates with the development of osteoarthritis -one of the most common complications in the aging population in Western countries. 54,56 iPSC-derived chondrocytes provide an alternative source for joint regeneration; therefore, the estimation of DNA stability and integrity is crucial before a therapeutic application. The differentiation process may induce differentiation-associated stress and increase DNA damage in iPSCs-derived cells.…”

Section: Dna Damage Response In Chondrogenesismentioning

confidence: 99%

“…Oxidative stress leads to telomere erosion, and increased expression of p53 and cyclindependent- kinase (CDK) inhibitors, p21 and p16INK4a (p16). 53 , 54 Moreover, senescent chondrocytes acquire a senescence-associated secretory phenotype characterized by a production of proinflammatory cytokines and matrix degrading enzymes, which further impair cartilage regeneration. It was shown that both, DNA damage and mitogenic stimuli by growth factors, are required to induce the persistent senescence in chondrocytes.…”

Section: Dna Damage Response In Chondrogenesismentioning

confidence: 99%

DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?

Sjakste

Riekstiņa²

2021

Eur J Histochem

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The review summarizes literature data on the role of DNA breaks and DNA repair in differentiation of pluripotent stem cells (PSC) and connective cell lineages. PSC, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), are rapidly dividing cells with highly active DNA damage response (DDR) mechanisms to ensure the stability and integrity of the DNA. In PSCs, the most common DDR mechanism is error-free homologous recombination (HR) that is primarily active during S phase of the cell cycle, whereas in quiescent, slow-dividing or non-dividing tissue progenitors and terminally differentiated cells, error-prone non-homologous end joining (NHEJ) mechanism of the double-strand break (DSB) repair is dominating. Thus, it seems that reprogramming and differentiation induce DNA strand breaks in stem cells which itself may trigger the differentiation process. Somatic cell reprogramming to iPSCs is preceded by a transient increase of the DSBs induced presumably by the caspase-dependent DNase or reactive oxygen species (ROS). In general, pluripotent stem cells possess stronger DNA repair systems compared to the differentiated cells. Nonetheless, during a prolonged cell culture propagation, DNA breaks can accumulate due to the DNA polymerase stalling. Consequently, the DNA damage might trigger the differentiation of stem cells or a replicative senescence of somatic cells. Differentiation process per se is often accompanied by a decrease of the DNA repair capacity. Thus, the differentiation might be triggered by DNA breaks, alternatively the breaks can be a consequence of the decay in the DNA repair capacity of differentiated cells.

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“…Expression of several of these metalloproteinases, as well as pro-inflammatory mediators, is induced by mechanical destabilization of the joint [9]. Additional factors including chondrocyte senescence [11], oxidative stress [12][13][14][15], and/or inflammation can also increase metalloproteinase expression and tip the balance towards cartilage breakdown.…”

Section: Introductionmentioning

confidence: 99%

Targeting Cartilage Degradation in Osteoarthritis

2021

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Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along with recent clinical trials on FGF18 and Wnt pathway inhibitors. We also considered dendrimer-based approaches being developed to deliver and retain such therapeutics in the joint environment. These may reduce systemic side effects while improving local half-life and concentration. Development of such targeted anabolic therapies would be of great benefit in the osteoarthritis field.

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Mechanisms and therapeutic implications of cellular senescence in osteoarthritis

Cited by 310 publications

References 123 publications

New Trends in Pharmacological Treatments for Osteoarthritis

New Trends in Pharmacological Treatments for Osteoarthritis

DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?

Targeting Cartilage Degradation in Osteoarthritis

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