The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis

He, Yuzhe; Wu, Zhipeng; Xu, Langhai; Xu, Kai; Chen, Zhonggai; Ran, Jisheng; Wu, Lidong

doi:10.1007/s00018-020-03497-9

Cited by 66 publications

(43 citation statements)

References 144 publications

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“…The protective effects on the mitochondria in chondrocytes that Irisin signaling facilitated did prompt us to verify the molecular mechanism underlying these events. Accumulating studies show that PCG-1α, UCP-1 and Sirt3 signaling are master regulators, indispensable in mitochondrial function, biogenesis and autophagy [52,53]. These mitochondrial regulators also mediate the Irisin promotion of tissue homeostasis [17,39].…”

Section: Discussionmentioning

confidence: 99%

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

Wang

Kuo

et al. 2020

Antioxidants

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Compromised autophagy and mitochondrial dysfunction downregulate chondrocytic activity, accelerating the development of osteoarthritis (OA). Irisin, a cleaved form of fibronectin type III domain containing 5 (FNDC5), regulates bone turnover and muscle homeostasis. Little is known about the effect of Irisin on chondrocytes and the development of osteoarthritis. This study revealed that human osteoarthritic articular chondrocytes express decreased level of FNDC5 and autophagosome marker LC3-II but upregulated levels of oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG) and apoptosis. Intra-articular administration of Irisin further alleviated symptoms of medial meniscus destabilization, like cartilage erosion and synovitis, while improved the gait profiles of the injured legs. Irisin treatment upregulated autophagy, 8-OHdG and apoptosis in chondrocytes of the injured cartilage. In vitro, Irisin improved IL-1β-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production by chondrocytes. Irisin also reversed Sirt3 and UCP-1 pathways, thereby improving mitochondrial membrane potential, ATP production, and catalase to attenuated IL-1β-mediated reactive oxygen radical production, mitochondrial fusion, mitophagy, and autophagosome formation. Taken together, FNDC5 loss in chondrocytes is correlated with human knee OA. Irisin repressed inflammation-mediated oxidative stress and extracellular matrix underproduction through retaining mitochondrial biogenesis, dynamics and autophagic program. Our analyses shed new light on the chondroprotective actions of this myokine, and highlight the remedial effects of Irisin on OA development.

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Section: Discussionmentioning

confidence: 99%

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

Wang

Kuo

et al. 2020

Antioxidants

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“…Recently, we found that SIRT3 could ameliorate osteoarthritis via regulating chondrocyte autophagy and apoptosis through the PI3K/Akt/mTOR pathway [ 37 ]. Besides, our previous study elaborated the vital role of SIRT3 in mitochondrial homeostasis in OA [ 21 ], and Wang et al and Chen et al further confirmed the protective role of SIRT3 in this condition [ 8 , 9 ]. In the present study, diverse experiments collectively verified that SIRT3 ameliorated osteoarthritis progression via reducing chondrocyte apoptosis as well as improving mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 80%

“…Rescues miR-505-3p-Induced Mitochondrial Dysfunction. In our previous review [21], we systematically elaborated the vital role of SIRT3 in mitochondrial homeostasis in OA. Since miR-505-3p was able to modulate SIRT3 expression, we considered that its role in mitochondrial metabolism and function was worthy of further research.…”

Section: Upregulation Of Sirt3mentioning

confidence: 99%

circFAM160A2 Promotes Mitochondrial Stabilization and Apoptosis Reduction in Osteoarthritis Chondrocytes by Targeting miR‐505‐3p and SIRT3

Bao

Lin

Zhou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Competitive endogenous RNAs (ceRNAs), as a newly identified regulating mechanism, have been demonstrated to play a crucial role in various human diseases. An increasing number of recent studies have revealed that circular RNAs (circRNAs) can function as ceRNAs. However, little is known about the role of circFAM160A2 in the pathological process of osteoarthritis (OA). This study is the first to examine the crucial role of the circFAM160A2-miR-505-3p-SIRT3 axis in osteoarthritis progression. miR-505-3p was selected from the interaction of a microRNA (miRNA) microarray comparing chondrocytes in OA and normal conditions and prediction results from TargetScan. RT-qPCR was performed to assess the expression of circFAM160A2, miR-505-3p, and SIRT3. A dual luciferase assay was used to validate the binding of circFAM160A2, miR-505-3p, and SIRT3. We used lentivirus and adeno-associated virus to establish in vitro and in vivo overexpression models. Western blotting, apoptosis assay, ROS detection assay, Safranin O staining, and CCK-8 assay were employed to assess the role of circFAM160A2, miR-505-3p, and SIRT3. We found that miR-505-3p was upregulated and circFAM160A2 was downregulated in OA. While overexpression of circFAM160A2 decreased the production of extracellular matrix (ECM) degrading enzymes and ameliorated chondrocyte apoptosis and mitochondrial dysfunction, inhibition of miR-505-3p could reverse the protective effect of circFAM160A2 on the OA phenotype both in vitro and in vivo. In conclusion, circFAM160A2 can promote mitochondrial stabilization and apoptosis reduction in OA chondrocytes by targeting miR-505-3p and SIRT3, which might be a potential therapeutic target for OA therapy.

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“…In addition to Sirt1, a recent study has highlighted the role of Sirt3-mediated mitochondrial homeostasis in OA. Sirt3, which is mainly located in mitochondria, can exert its deacetylation activity to regulate mitochondrial function, regeneration, and dynamics (He et al, 2020). Mitochondrial dysfunction-induced chondrocyte phenotypic inflammatory and matrix degradation responses also occur via ROS-mediated activation of c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK)/cFos-AP1 pathways in chondrocytes of osteoarthritic and aged cartilage (Ansari et al, 2020).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Chondrocyte Aging: The Molecular Determinants and Therapeutic Opportunities

Ramasamy

Yee

Khan

2021

Front. Cell Dev. Biol.

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Osteoarthritis (OA) is a joint degenerative disease that is an exceedingly common problem associated with aging. Aging is the principal risk factor for OA, but damage-related physiopathology of articular chondrocytes probably drives the mechanisms of joint degeneration by a progressive decline in the homeostatic and regenerative capacity of cells. Cellular aging is the manifestation of a complex interplay of cellular and molecular pathways underpinned by transcriptional, translational, and epigenetic mechanisms and niche factors, and unraveling this complexity will improve our understanding of underlying molecular changes that affect the ability of the articular cartilage to maintain or regenerate itself. This insight is imperative for developing new cell and drug therapies for OA disease that will target the specific causes of age-related functional decline. This review explores the key age-related changes within articular chondrocytes and discusses the molecular mechanisms that are commonly perturbed as cartilage ages and degenerates. Current efforts and emerging potential therapies in treating OA that are being employed to halt or decelerate the aging processes are also discussed.

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The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis

Cited by 66 publications

References 144 publications

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

circFAM160A2 Promotes Mitochondrial Stabilization and Apoptosis Reduction in Osteoarthritis Chondrocytes by Targeting miR‐505‐3p and SIRT3

Chondrocyte Aging: The Molecular Determinants and Therapeutic Opportunities

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