Autophagy activation by rapamycin reduces severity of experimental osteoarthritis

Caramés, Beatriz; Hasegawa, Akihiko; Taniguchi, Noboru; Miyaki, Shigeru; Blanco, Francisco J.; Lotz, Martin

doi:10.1136/annrheumdis-2011-200557

Cited by 375 publications

(411 citation statements)

References 44 publications

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“…Genetic ablation of cartilage mTOR (47) or inhibition of mTOR with the drug rapamycin (48,49) reduces the expression of catabolic enzymes and maintains cartilage viability in experimental OA. Here we establish that mTORC1 is activated early (within 24 h) in chondrocytes following a mechanical injury.…”

Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

114

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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

114

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“…We suspected that healthy chondrocytes, which reside in a naturally hypoxic avascular environment, may have high baseline levels of autophagy. There is increasing evidence that defective autophagy contributes to the development of osteoarthritis (15)(16)(17). Given the role autophagy plays in release of extracellular vesicles, we hypothesized that autophagy could promote ACV formation and release in primary articular chondrocyte cultures.…”

mentioning

confidence: 99%

Autophagy Modulates Articular Cartilage Vesicle Formation in Primary Articular Chondrocytes

Rosenthal

Gohr

Mitton-Fitzgerald

et al. 2015

Journal of Biological Chemistry

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Background: Articular cartilage vesicles (ACVs) participate in cell communication, protein secretion, and pathologic mineralization. Results: ACV release from chondrocytes is regulated in concert with autophagy and is caspase-3-and Rho/ROCK-dependent. Conclusion: Autophagy participates in chondrocyte ACV release. Significance: This work identifies a potential mechanism of ACV formation and presents opportunities to manipulate quantity and content of these important organelles.

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“…Cell death diminishes the ability of cells to proliferate, mainly due to an increase in apoptosis, which is thought to be a major cause of chondrocyte depletion during OA progression. Several studies have demonstrated that another type of cell death, autophagy, is involved in chondrocyte depletion during OA progression (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Tougu Xiaotong capsule promotes chondrocyte autophagy by regulating the Atg12/LC3 conjugation systems

Li¹,

Liu²,

Liang³

et al. 2014

International Journal of Molecular Medicine

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Abstract. We have previously reported that Tougu Xiaotong capsule (TXC) inhibits tidemark replication and cartilage degradation by regulating chondrocyte autophagy in vivo. Autophagy, a cell protective mechanism for maintaining cellular homeostasis, has been shown to be a constitutively active and protective process for chondrocyte survival. However, it remains unclear whether TXC promotes chondrocyte autophagy by regulating the autophagy-related (Atg)12/microtubuleassociated protein 1 light chain 3 (LC3) conjugation systems. Thus, in the present study, we investigated the effects of TXC on primary chondrocytes treated with cobalt chloride (CoCl 2 ). We found that CoCl 2 induced a decrease in chondrocyte viability and the autophagosome formation of chondrocytes, indicating that CoCl 2 induced autophagic death in a dose-and time-dependent manner. To determine the effects of TXC on CoCl 2 -exposed chondrocytes, we assessed cell viability by MTT assay. Our results revealed that TXC enhanced the viability of CoCl 2 -exposed chondrocytes. To gain insight into the mechanisms responsible for the enhancing effects of TXC on CoCl 2 -exposed chondrocytes, the expression of Atg genes was assessed in chondrocytes exposed to CoCl 2 and treated with or without TXC. The results revealed that the expression of beclin 1, Atg3, Atg5, Atg7, Atg10, Atg12 and LC3 II/LC3 I in the chondrocytes treated with TXC increased, compared to that in the untreated chondrocytes. In addition, ultrastructural analysis indicated that treated chondrocytes contained more autophagosomes than the untreated cells, suggesting that TXC increased the formation of autophagosomes in the chondrocytes to clear the CoCl 2 -induced autophagic death. Therefore, these data suggest that TXC is a potential therapeutic agent for the reduction of cartilage degradation that occurs in osteoarthritis.

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Autophagy activation by rapamycin reduces severity of experimental osteoarthritis

Cited by 375 publications

References 44 publications

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Autophagy Modulates Articular Cartilage Vesicle Formation in Primary Articular Chondrocytes

Tougu Xiaotong capsule promotes chondrocyte autophagy by regulating the Atg12/LC3 conjugation systems

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