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J Bone Miner Res. 2019 May 10. doi: 10.1002/jbmr.3756. [Epub ahead of print]

Beclin1 modulates bone homeostasis by regulating osteoclast and chondrocyte differentiation.

Arai A1,2,3, Kim S1, Goldshteyn V1, Kim T1, Park NH1,4,5, Wang CY2,4, Kim R1,4.

Author information

1
Shapiro Family Laboratory of Viral Oncology and Aging Research, UCLA School of Dentistry, Los Angeles, CA, USA.
2
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA.
3
Institute for Oral Science, Department of Orthodontics, Matsumoto Dental University, Nagano, Japan.
4
UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
5
UCLA David Geffen School of Medicine, Los Angeles, CA, USA.

Abstract

Autophagy, an important cellular recycling process whereby macromolecules or organelles are encapsulated by autophagosome and degraded upon merging with lysosome, is recently shown to play an essential role in bone biology. However, the involvement of autophagy in bone and bone-related cells remains unclear. Here, we show that Beclin1, an autophagy-related (ATG) protein involved in autophagy initiation, plays a pivotal role in osteoclasts. Autophagy was activated during osteoclast differentiation in vitro. Beclin1 was enhanced and required for osteoclast differentiation. Mechanistically, we found that TRAF6-mediated ubiquitination of Beclin1 at K117, but not ULK1-mediated phosphorylation, is required for RANKL-stimulated osteoclast differentiation. In vivo, mice lacking Becn1 in CstK-expressing cells exhibited in increased cortical bone thickness due to impaired osteoclasts' function. Interestingly, these mice also exhibited diminished trabecular bone mass, which was associated with defect in cartilage formation and chondrocyte differentiation. Collectively, our study highlights the functional importance of autophagy in osteoclasts and chondrocytes, and identifies autophagy as a potential therapeutic target for managing bone-related diseases. This article is protected by copyright. All rights reserved.

KEYWORDS:

Beclin1; RANKL; autophagy; chondrocytes; osteoclasts; ubiquitination

PMID:
31074883
DOI:
10.1002/jbmr.3756

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