Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis

Álvarez-García, Óscar; Matsuzaki, Takashi; Olmer, Merissa; Plate, Lars; Kelly, Jeffery W.; Lotz, Martin

doi:10.1002/art.40104

Cited by 72 publications

(59 citation statements)

References 49 publications

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“…In previous years, substantial progress has been made toward the elucidation of the underlying mechanism and the development of effective treatments for the pathological progression in established OA ( 22 ). Studies have demonstrated that diseases associated with aging may result from failure of cellular homeostasis mechanisms, including autophagy, which lead to changes in gene expression patterns and extracellular matrix destruction ( 23 , 24 ). Thus, the present study explored whether autophagy is involved in the pathogenesis of OA and demonstrated markedly reduced autophagy in the knee joints of murine OA models.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1

Miao

Zhu

et al. 2017

Exp Ther Med

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Autophagy has been reported to be widely involved in the pathogenesis of osteoarthritis (OA). Increasing evidence suggested the important role of microRNAs (miRs) in the progression of OA. However, the functional role of miR-17-5p in OA development has remained to be fully elucidated. First, a mouse model of OA was established and the relative level of miR-17-5p was determined using PCR. Safranin O-fast green staining was applied to determine cartilage degeneration. TargetScan software and a dual luciferase reporter assay were applied to determine potential target genes of miR-17-5P. Autophagy measurement was performed using green fluorescent protein-microtubule-associated protein 1 light chain 3 (LC3) dot analysis. The results demonstrated that the relative expression of miR-17-5p was significantly decreased in OA model mice. In addition, the level of miR-17-5p was decreased in SW1353 human chondrosarcoma cells treated with interleukin-1β. Furthermore, autophagy was found to be suppressed in the knee joints of experimental OA model mice. The dual luciferase reporter assay confirmed that p62/sequestosome 1 was a target gene of miR-17-5p. Of note, miR-17-5p inhibitor-induced reduction of LC3 dots was markedly reversed by knockdown of p62 in SW1353 cells. In conclusion, decreased miR-17-5p expression in chondrocytes induced autophagy mainly through suppressing the expression of p62, thereby contributing to OA progression.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1

Miao

Zhu

et al. 2017

Exp Ther Med

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“…Protein extraction and Western blotting were performed as described previously (Alvarez‐Garcia, Matsuzaki, Olmer, Plate, et al, 2017). Specific antibodies used were FOXO1 (1:1,000; 2,880 T; Cell Signaling Technology, Danvers, MA, USA), FOXO3 (1:1,000; 2497S; Cell Signaling Technology), LC3 (1:1,000; 12,741 T; Cell Signaling Technology), p62 (SQSTM1, 8025S; 1:1,000; Cell Signaling Technology), HIF1A (1:1,000; 20960‐1‐AP; Proteintech) β‐tubulin (1:2,000; 66240‐1‐Ig; Proteintech), and GAPDH (1:5,000; AM4300; Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

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“…An intriguing potential factor in this regard is REDD1, which is up-regulated in response to hypoxia and energy stress, and functions as a pleiotropic regulator of cell metabolism (Ellisen 2005;Gordon et al 2016b;Lipina and Hundal 2016). Both mammalian REDD1 and its Drosophila orthologs inhibit TORC1 kinase activity in the acute response to hypoxia (Brugarolas et al 2004;Reiling and Hafen 2004), while genetic and biochemical studies have demonstrated both mTORC1-dependent and TORC1-independent roles for REDD1 in control of glycolysis, autophagy, and mitochondrial oxidative metabolism (DeYoung et al 2008;Horak et al 2010;Qiao et al 2015;Gordon et al 2016a;Alvarez-Garcia et al 2017). Phenotypes associated with REDD1 genetic loss support its role as a physiological mediator of diverse pathologic cellular stress responses.…”

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confidence: 99%

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

et al. 2020

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Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROSdetoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

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Regulated in Development and DNA Damage Response 1 Deficiency Impairs Autophagy and Mitochondrial Biogenesis in Articular Cartilage and Increases the Severity of Experimental Osteoarthritis

Cited by 72 publications

References 49 publications

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1

MicroRNA-17-5p contributes to osteoarthritis progression by binding p62/SQSTM1

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

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