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Osteoarthritis Cartilage. 2016 Sep;24(9):1639-47. doi: 10.1016/j.joca.2016.04.015. Epub 2016 Apr 23.

Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy.

Author information

1
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; Department of Orthopaedic Surgery, School of Medicine, Chiba University, 1-8-1, Inohana, Chuou, Chiba, 260-8677, Japan.
3
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: mlotz@scripps.edu.

Abstract

OBJECTIVE:

Aging is a main risk factor for the development of osteoarthritis (OA) and the molecular mechanisms underlying the aging-related changes in articular cartilage include increased mammalian target of rapamycin (mTOR) signaling and defective autophagy. REDD1 is an endogenous inhibitor of mTOR that regulates cellular stress responses. In this study we measured REDD1 expression in normal, aged and OA cartilage and assessed REDD1 function in human and mouse articular chondrocytes.

METHODS:

REDD1 expression was analyzed in human and mouse articular cartilage by qPCR, western blotting, and immunohistochemistry. For functional studies, REDD1 and TXNIP knockdown or overexpression was performed in chondrocytes in the presence or absence of rapamycin and chloroquine, and mTOR signaling and autophagy were measured by western blotting. REDD1/TXNIP protein interaction was assessed by co-immunoprecipitation experiments.

RESULTS:

Human and mouse cartilage from normal knee joints expressed high levels of REDD1. REDD1 expression was significantly reduced in aged and OA cartilage. In cultured chondrocytes, REDD1 knockdown increased whereas REDD1 overexpression decreased mTOR signaling. In addition, REDD1 activated autophagy by an mTOR independent mechanism that involved protein/protein interaction with TXNIP. The REDD1/TXNIP complex was required for autophagy activation in chondrocytes.

CONCLUSION:

The present study shows that REDD1 is highly expressed in normal human articular cartilage and reduced during aging and OA. REDD1 in human chondrocytes negatively regulates mTOR activity and is essential for autophagy activation. Reduced REDD1 expression thus represents a novel mechanism for the increased mTOR activation and defective autophagy observed in OA.

KEYWORDS:

Autophagy; Cartilage; Osteoarthritis; REDD1; mTOR

PMID:
27118398
PMCID:
PMC4992644
DOI:
10.1016/j.joca.2016.04.015
[Indexed for MEDLINE]
Free PMC Article

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