Mitophagy in degenerative joint diseases

Sun, Kai; Jing, Xingzhi; Guo, Jiachao; Yao, Xudong; Guo, Fengjing

doi:10.1080/15548627.2020.1822097

Cited by 242 publications

(155 citation statements)

References 107 publications

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“…30,31 Mitophagy, which represents the selective uptake of mitochondria by autophagosomes of the cells, has been observed as a correlate of mitochondrial disturbances in OA. 32,33 In addition, apoptosis in OA can be induced by lysosomal dysfunction as recently reported. 34 Enhanced cell death and ECM degradation propagate the presence of damage products including so-called alarmins, some of them released from the cytosol.…”

mentioning

confidence: 73%

Experimental Therapeutics for the Treatment of Osteoarthritis

Schulze‐Tanzil

2021

JEP

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Osteoarthritis (OA) therapy remains a large challenge since no causative treatment options are so far available. Despite some main pathways contributing to OA are identified its pathogenesis is still rudimentary understood. A plethora of therapeutically promising agents are currently tested in experimental OA research to find an opportunity to reverse OA-associated joint damage and prevent its progression. Hence, this review aims to summarize novelly emerging experimental approaches for OA. Due to the diversity of strategies shown only main aspects could be summarized here including herbal medicines, nanoparticular compounds, growth factors, hormones, antibody-, cell-and extracellular vesicle (EV)-based approaches, optimized tools for joint viscosupplementation, genetic regulators such as si-or miRNAs and promising combinations. An abundant multitude of compounds obtained from plants, environmental, autologous or synthetic sources have been identified with anabolic, anti-inflammatory,-catabolic and anti-apoptotic properties. Some ubiquitous signaling pathways such as wingless and Integration site-1 (Wnt), Sirtuin, Tolllike receptor (TLR), mammalian target of rapamycin (mTOR), Nuclear Factor (NF)-κB and complement are involved in OA and addressed by them. Hyaluronan (HA) provided benefit in OA since many decades, and novel HA formulations have been developed now with higher HA content and long-term stability achieved by cross-linking suitable to be combined with other agents such as components from herbals or chemokines to attract regenerative cells. pH-or inflammation-sensitive nanoparticular compounds could serve as versatile slowrelease systems of active compounds, for example, miRNAs. Some light has been brought into the intimate regulatory network of small RNAs in the pathogenesis of OA which might be a novel avenue for OA therapy in future. Attraction of autologous regenerative cells by chemokines and exosome-based treatment strategies could also innovate OA therapy.

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mentioning

confidence: 73%

Experimental Therapeutics for the Treatment of Osteoarthritis

Schulze‐Tanzil

2021

JEP

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“…In contrast, LC3B and LAMP1 levels were regulated by UA treatment. LC3B, a common autophagosome marker, is a central protein in the autophagy pathway, functioning in autophagy substrate selection and autophagosome biogenesis (Sun et al, 2020). LAMP1 is a lysosomal membrane protein, which is responsible for maintaining lysosomal integrity, pH, catabolism, and forming autophagy-lysosomal organelles (Eskelinen 2006).…”

Section: Discussionmentioning

confidence: 99%

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Yocum

Alexander

et al. 2021

Front. Pharmacol.

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Physiological mechanical stimulation has been shown to promote chondrogenesis, but excessive mechanical loading results in cartilage degradation. Currently, the underlying mechanotransduction pathways in the context of physiological and injurious loading are not fully understood. In this study, we aim to identify the critical factors that dictate chondrocyte response to mechanical overloading, as well as to develop therapeutics that protect chondrocytes from mechanical injuries. Specifically, human chondrocytes were loaded in hyaluronic hydrogel and then subjected to dynamic compressive loading under 5% (DL-5% group) or 25% strain (DL-25% group). Compared to static culture and DL-5%, DL-25% reduced cartilage matrix formation from chondrocytes, which was accompanied by the increased senescence level, as revealed by higher expression of p21, p53, and senescence-associated beta-galactosidase (SA-β-Gal). Interestingly, mitophagy was suppressed by DL-25%, suggesting a possible role for the restoration mitophagy in reducing cartilage degeneration with mechanical overloading. Next, we treated the mechanically overloaded samples (DL-25%) with Urolithin A (UA), a natural metabolite previously shown to enhance mitophagy in other cell types. qRT-PCR, histology, and immunostaining results confirmed that UA treatment significantly increased the quantity and quality of cartilage matrix deposition. Interestingly, UA also suppressed the senescence level induced by mechanical overloading, demonstrating its senomorphic potential. Mechanistic analysis confirmed that UA functioned partially by enhancing mitophagy. In summary, our results show that mechanical overloading results in cartilage degradation partially through the impairment of mitophagy. This study also identifies UA’s novel use as a compound that can protect chondrocytes from mechanical injuries, supporting high-quality cartilage formation/maintenance.

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“…While there have been some treatments shown to provide temporary pain relief in the setting of tendinopathy, healing damaged tendons is still a challenging clinical problem. After the discovery of the regulation of mitochondrial energy production, 94,95 scientists considered the role and function that mitochondria might serve in a variety of disease processes, including chronic metabolic diseases, such as obesity and type 2 diabetes mellitus; 96 infantile‐onset debilitating disorders, such as Barth syndrome; 97 multiple degenerative diseases, such as intervertebral disc degeneration and osteoarthritis, 98 and began developing drugs specifically targeting mitochondria to promote healing and recovery. The rationale for developing drugs to target mitochondria lies in the following mitochondrial functions: (1) preventing oxidative damage (antioxidant); (2) modulation of metabolism; (3) mitochondrial permeability transition pore inhibition; and (4) inhibition of specific ROS levels (Fig.…”

Section: Mitochondrial Protectants As Therapeutic Agentsmentioning

confidence: 99%

Mitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy

Zhang

Eliasberg

Rodeo

2021

Annals of the New York Academy of Sciences

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Tendinopathy is a common musculoskeletal condition that affects a wide range of patients, including athletes, laborers, and older patients. Tendinopathy is often characterized by pain, swelling, and impaired performance and function. The etiology of tendinopathy is multifactorial, including both intrinsic and extrinsic mechanisms. Various treatment strategies have been described, but outcomes are often variable, as tendons have poor intrinsic healing potential compared with other tissues. Therefore, several novel targets for tendon regeneration have been identified and are being explored. Mitochondria are organelles that generate adenosine triphosphate, and they are considered to be the power generators of the cell. Recently, mitochondrial dysfunction verified by increased reactive oxygen species (ROS), decreased superoxide dismutase activity, cristae disorganization, and decreased number of mitochondria has been identified as a mechanism that may contribute to tendinopathy. This has provided new insights for studying tendinopathy pathogenesis and potential treatments via antioxidant, metabolic modulation, or ROS inhibition. In this review, we present the current understanding of mitochondrial dysfunction in tendinopathy. The review summarizes the potential mechanism by which mitochondrial dysfunction contributes to the development of tendinopathy, as well as the potential therapeutic benefits of mitochondrial protectants in the treatment of tendinopathy.

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Mitophagy in degenerative joint diseases

Cited by 242 publications

References 107 publications

Experimental Therapeutics for the Treatment of Osteoarthritis

Experimental Therapeutics for the Treatment of Osteoarthritis

Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries

Mitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy

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