Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation

Abstract

Autophagy (ATG), an important cellular recycling process whereby macromolecules or organelles are encapsulated by autophagosome and degraded upon merging with lysosome, has recently been shown to play an essential role in bone biology. However, the involvement of ATG in bone and bone‐related cells remains unclear. Here, we show that Beclin1, an ATG‐related protein involved in ATG initiation, plays a pivotal role in osteoclasts. ATG 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 Beclin1 in CstK‐expressing cells exhibited an increased cortical bone thickness caused by impaired osteoclasts’ function. Interestingly, these mice also exhibited diminished trabecular bone mass, which was associated with a defect in cartilage formation and chondrocyte differentiation. Collectively, our study highlights the functional importance of ATG in osteoclasts and chondrocytes, and identifies ATG as a potential therapeutic target for managing bone‐related diseases. © 2019 American Society for Bone and Mineral Research.

Autophagy in spinal ligament fibroblasts: evidence and possible implications for ossification of the posterior longitudinal ligament

“…Notably, Beclin1 expression was correlated with the expression of osteogenic differentiation markers OCN, ALP and COL 1 in patients with OPLL. Consistently, a recent study reported that Beclin1 plays an important role in the differentiation of osteoclasts and chondrocytes [9]. To con rm the role of Beclin1 in broblasts, siRNA targeting Beclin1 was designed and used to downregulate the expression of Beclin1.…”

“…Autophagy, a macromolecular degradation process, plays a pivotal role in the maintenance of cell differentiation [9]. Autophagy of osteocytes was rst con rmed by Zahm et al [10], and subsequent studies had reported that autophagic receptor and Unc-51 like autophagy activating kinase 1 (ULK1) had an important effect on the activity and differentiation of osteoblasts [11][12][13].…”

Impaired autophagy triggered by HDAC9 in mesenchymal stem cells accelerates bone mass loss

“…Recent studies have indicated that autophagy is a key process in bone cells differentiation. It has been reported that autophagy can regulate osteoclast and chondrocyte differentiation [37], and protect BMMSCs from oxidative stress [38], which indicates that autophagy plays protective roles in maintaining bone homeostasis. Our previous study also showed that impaired autophagy triggers intracellular ROS-induced senescence in BMMSCs, which shifts cellular lineage commitment from osteoblasts to adipocytes, consequently leading to bone aging [20,21].…”

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“…Adolph et al reported that mice with epithelial specific compromised UPR (XBP1) and autophagy function (ATG16L1) spontaneously developed severe CD-like transmural ileitis [182], accompanied with NF-κB overactivation-mediated intestinal inflammation. Several studies revealed regulation of autophagy on bone cell development and function, as well as the effects of autophagy on bone microenvironment are context-dependent [183][184][185][186][187]. Wu et al reported that IEC-specific VDR regulated ATG16L1 level at both transcriptional and translational level [188].…”