Autophagy plays an essential role in bone homeostasis

Jaber, Fatima A.; Khan, Nazir M.; Ansari, Mohammad Y.; Al-Adlaan, Asaad A; Hussein, Nazar; Safadi, Fayez F.

doi:10.1002/jcp.27071

Cited by 43 publications

(40 citation statements)

References 108 publications

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“…Previous study showed that ATP6V0D2 is identified as a key component of autophagosome-lysosome fusion machinery in macrophages, which is required for the macrophage-specific completion of autophagy [53]. Autophagy is a cellular self-protection mechanism and plays an important role in osteoclast differentiation and function [54][55][56]. However, whether Atp6v0d2 takes effect in the modulation of osteoclast autophagy remains unclear.…”

Section: Discussionmentioning

confidence: 99%

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

Cai

Meng

et al. 2020

IJMS

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Osteoclast differentiation and function are crucial for maintaining bone homeostasis and preserving skeletal integrity. N6-methyladenosine (m6A) is an abundant mRNA modification that has recently been shown to be important in regulating cell lineage differentiation. Nevertheless, the effect of m6A on osteoclast differentiation remains unknown. In the present study, we observed that the m6A level and methyltransferase METTL3 expression increased during osteoclast differentiation. Mettl3 knockdown resulted in an increased size but a decreased bone-resorbing ability of osteoclasts. The expression of osteoclast-specific genes (Nfatc1, c-Fos, Ctsk, Acp5 and Dcstamp) was inhibited by Mettl3 depletion, while the expression of the cellular fusion-specific gene Atp6v0d2 was upregulated. Mechanistically, Mettl3 knockdown elevated the mRNA stability of Atp6v0d2 and the same result was obtained when the m6A-binding protein YTHDF2 was silenced. Moreover, the phosphorylation levels of key molecules in the MAPK, NF-κB and PI3K-AKT signaling pathways were reduced upon Mettl3 deficiency. Depletion of Mettl3 maintained the retention of Traf6 mRNA in the nucleus and reduced the protein levels of TRAF6. Taken together, our data suggest that METTL3 regulates osteoclast differentiation and function through different mechanisms involving Atp6v0d2 mRNA degradation mediated by YTHDF2 and Traf6 mRNA nuclear export. These findings elucidate the molecular basis of RNA epigenetic regulation in osteoclast development.

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Section: Discussionmentioning

confidence: 99%

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

Cai

Meng

et al. 2020

IJMS

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“…HDAC inhibitors have been proposed as promising anti-aging drugs. In this study, we found modulating Autophagy is a very important degradation system, playing a crucial role in maintaining cell homeostasis in response to cellular stress [35,36]. Autophagy dysfunction is associated with several diseases, such as inflammation, cancer, neurodegeneration and aging [36].…”

Section: Discussionmentioning

confidence: 79%

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

Zhang

Meng

Chen

et al. 2020

Preprint

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Abstract Background: Bone mass loss in aging is linked with imbalanced lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs). Recent studies have proved that histone deacetylases (HDACs) are regarded as key regulators of bone remodeling. However, HDACs involve in regulating BMMSCs bio-behaviors remain elusive. Here, we investigated ability of HDAC9 on modulation of autophagy and its significance in lineage differentiation of BMMSCs. Methods: The effects of HDAC9 on lineage differentiation of BMMSCs and autophagic signalling were assessed by various biochemical (Western blot and ChIP assay), morphological (TEM and confocal microscopy) and microCT assays. Results：16-month mice manifested obvious bone mass loss and marrow fat increase, accompanied with the decreased osteogenic differentiation and increased adipogenic differentiation of BMMSCs. Further, the expression of HDAC9 elevated in bone and BMMSCs. Importantly, HDAC9 inhibitors recovered the lineage differentiation of 16-month BMMSCs and reduced p53 expression. Mechanistically, we revealed that HDAC9 regulated the autophagy of BMMSCs by controlling H3K9 acetylation in the promoters of the autophagic genes, ATG7 , BECN1 , and LC3a/b, which subsequently affected their lineage differentiation. Finally, HDAC9 inhibition improved endogenous BMMSCs properties and promoted the bone mass recovery of 16-month mice. Conclusions: Our data demonstrate that HDAC9 is a key regulator in variety of bone mass by regulating autophagic activity in BMMSCs and is thus, a potential target of age-related bone loss treatment.

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“…The main reason for this could be that cells were derived from different populations. Previous data suggests that autophagy is essential for osteogenic differentiation [18]. To con rm the results at the tissue level, the mRNA and protein expression of autophagy related genes were further analyzed in ligament broblasts derived from OPLL and non-OPLL patients.…”

Section: Discussionmentioning

confidence: 81%

“…Furthermore, our previous results revealed that the level of osteocyte autophagy was associated with bone loss in ovariectomized rats and aged rats [15][16][17]. Hitherto, it is generally accepted that autophagy plays an essential role in the osteogenic differentiation of mesenchymal stem cells [14,18]. However, autophagy of spinal ligament broblast has not yet been investigated and the underlying role of autophagy in OPLL processes remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Lin

Chen

et al. 2020

Preprint

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Background: The molecular mechanisms of ossification of the posterior longitudinal ligament (OPLL) remains to be elucidated. The aim of the present study was to investigate the autophagy of spinal ligament fibroblasts derived from patients with OPLL and to examine whether autophagy associated gene expression was correlated with the expression of osteogenic differentiation genes. Methods: Expression of autophagy associated genes was detected in 37 samples from 21 OPLL patients and 16 non-OPLL patients. The correlation of autophagy associated gene expression and the expression of osteogenic differentiation genes was analyzed by Pearson’s correlation. The expression of autophagy associated genes of ligament fibroblasts was assessed by reverse transcription-quantitative Polymerase Chain Reaction (RT-qPCR), western blotting and immunofluorescence. The incidence of autophagy was assessed by flow cytometry. After knockdown using small interfering RNA targeting Beclin1, the expression of osteogenic differentiation genes were compared in spinal ligament fibroblasts. Results: In clinical specimens, mRNA expression levels of microtubule-associated protein 1 light chain 3 and Beclin1 were higher in the OPLL group compared with the non-OPLL group. Pearson correlation analysis demonstrated that Beclin1 expression was positively correlated with expression of osteocalcin (OCN) (r=0.8233, P<0.001), alkaline phosphatase, biomineralization associated (ALP) (r=0.7821, P<0.001) and collagen type 1 (COL 1) (r=0.6078, P=0.001). Consistently, the upregulation of autophagy associated genes in ligament fibroblasts from patients with OPLL were further confirmed by western blotting and immunofluorescence. The incidence of autophagy was also increased in ligament fibroblasts from patients with OPLL. Furthermore, knockdown of Beclin1 led to a decrease in the expression of OCN, ALP and COL 1 by 63.2% (P<0.01), 52% (P<0.01) and 53.2% (P<0.01) in ligament fibroblasts from patients with OPLL, respectively. Conclusions: Beclin1-mediated autophagy was involved in the osteogenic differentiation of ligament fibroblasts, and promoted the development of OPLL.

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Autophagy plays an essential role in bone homeostasis

Abstract: Autophagy is very critical for multiple cellular processes. Autophagy plays a critical role in bone cell differentiation and function.

Cited by 43 publications

References 108 publications

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

METTL3 Modulates Osteoclast Differentiation and Function by Controlling RNA Stability and Nuclear Export

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

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

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