Osteolineage depletion of mitofusin2 enhances cortical bone formation in female mice

Zarei, Allahdad; Ballard, Anna; Cox, Linda; Bayguinov, Peter O.; Harris, Taylor L.; Davis, Jennifer L.; Roper, Philip M.; Faccio, Roberta; Veis, Deborah J.

doi:10.1016/j.bone.2021.115941

Cited by 6 publications

(7 citation statements)

References 46 publications

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“…There are few studies on MFN2 and osteogenic differentiation. The lack of Mfn2 in the mouse osteoblast lineage enhances the formation of basal bone in vivo and in vitro by increasing the number of osteoblasts and osteogenic differentiation capability [ 12 ]. The expression of MFN2 and the endoplasmic reticulum-mitochondrial coupling increase in the inflammatory microenvironment, leading to impaired osteogenic differentiation of periodontal ligament stem cells [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, MFN2 knockdown significantly increases the expression of genes encoding glycolytic enzymes and glycolytic metabolites [ 11 ]. In the early stage of osteogenesis, the lack of Mfn2 enhances the osteogenic differentiation and cortical bone accumulation of mice in vitro and in vivo [ 12 ]. These findings indicate that MFN2 ablation may promote the conversion of glycolytic bioenergy to meet the energy requirements of specific cells such as osteoblasts.…”

Section: Introductionmentioning

confidence: 99%

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MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway

Deng¹,

Yi²,

Yin³

et al. 2022

Stem Cell Res Ther

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Background Mitofusin-2 (MFN2) is a kind of GTPase that participates in the regulation of mitochondrial fusion, which is related to a variety of physiological and pathological processes, including energy metabolism, cell differentiation, and embryonic development. However, it remains unclear whether MFN2 is involved in the metabolism and osteogenic differentiation of mesenchymal stem cells (MSCs). Methods MFN2 knockdown (MFN2-KD) and MFN2-overexpressing (MFN2-OE) induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) were constructed by lentivirus. The commercial kits were utilized to detect the glycolysis and oxidative phosphorylation (OXPHOS) rate. Flow cytometry, Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), RNA-seq, immunofluorescence, and immunoprecipitation were employed for phenotype and molecular mechanism assessment. Results We demonstrated that MFN2 and Wnt/β-catenin signaling pathway regulated glycolysis of iPSC-MSCs. The lack of MFN2 promoted the osteogenic differentiation of iPSC-MSCs, and aerobic glycolysis in the presence of sufficient oxygen, which increased glucose consumption and lactic acid production, as well as the glycolytic enzyme activity and gene expression. Inhibiting the Wnt/β-catenin signaling pathway normalized the enhanced glycolytic rate and osteogenic differentiation of MFN2-KD iPSC-MSCs. MFN2-OE iPSC-MSCs displayed the opposite phenotype. Conclusions Downregulating MFN2 promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway. Our research reveals the new function of MFN2 in regulating the osteogenic differentiation and energy metabolism of MSCs, which will provide a new therapeutic target and theoretical basis for alveolar bone repair and periodontal regenerative treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway

Deng¹,

Yi²,

Yin³

et al. 2022

Stem Cell Res Ther

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“…We found that the increased apoptosis of osteoblasts/osteocytes was significantly coupled with reduced autophagy activity after DDR1 deletion in osteoblasts, contributing to a reduction of bone formation during adulthood. The formation of the cortical bone is more related to the osteoblasts in the periosteum, with few roles for osteoclasts [ 44 , 45 ]. Therefore, we also noted a significant decrease in the thickness of the cortical bone after DDR1 deletion in osteoblasts/osteocytes.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

et al. 2022

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Discoidin domain receptor 1 (DDR1) is a collagen receptor that belongs to the receptor tyrosine kinase family. We have previously shown that DDR1 plays a crucial role during bone development, resulting in dwarfism and a short stature in osteoblast-specific knockout mice (OKO mice). However, the detailed pathophysiological effects of DDR1 on bone development throughout adulthood have remained unclear. This study aims to identify how DDR1 regulates osteoblast and osteocyte functions in vivo and in vitro during bone development in adulthood. The metabolic changes in bone tissues were analyzed using Micro-CT and immunohistochemistry staining (IHC) in vivo; the role of DDR1 in regulating osteoblasts was examined in MC3T3-E1 cells in vitro. The Micro-CT analysis results demonstrated that OKO mice showed a 10% reduction in bone-related parameters from 10 to 14 weeks old and a significant reduction in cortical thickness and diameter compared with flox/flox control mice (FF) mice. These results indicated that DDR1 knockout in OKO mice exhibiting significant bone loss provokes an osteopenic phenotype. The IHC staining revealed a significant decrease in osteogenesis-related genes, including RUNX2, osteocalcin, and osterix. We noted that DDR1 knockout significantly induced osteoblast/osteocyte apoptosis and markedly decreased autophagy activity in vivo. Additionally, the results of the gain- and loss-of-function of the DDR1 assay in MC3T3-E1 cells indicated that DDR1 can regulate the osteoblast differentiation through activating autophagy by regulating the phosphorylation of the mechanistic target of rapamycin (p-mTOR), light chain 3 (LC3), and beclin-1. In conclusion, our study highlights that the ablation of DDR1 results in cancellous bone loss by regulating osteoblast/osteocyte autophagy. These results suggest that DDR1 can act as a potential therapeutic target for managing cancellous bone loss.

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“…These findings suggest potential defects in bone remodelling, in line with recent studies that demonstrated a role of Mfn2 in bone development. 66,67 Overall, the ENU-induced MFN2 L643P transgenic model presented a recessive mild neuromuscular phenotype in mice, coupled with mild skeletal and mitochondrial abnormalities.…”

Section: Enu-inducedmfn2 L643p Transgenicmodelmentioning

confidence: 99%

Charcot–Marie‐Tooth type 2A in vivo models: Current updates

Abati,

Rizzuti,

Anastasia

et al. 2024

J Cellular Molecular Medi

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Charcot–Marie‐Tooth type 2A (CMT2A) is an inherited sensorimotor neuropathy associated with mutations within the Mitofusin 2 (MFN2) gene. These mutations impair normal mitochondrial functioning via different mechanisms, disturbing the equilibrium between mitochondrial fusion and fission, of mitophagy and mitochondrial axonal transport. Although CMT2A disease causes a significant disability, no resolutive treatment for CMT2A patients to date. In this context, reliable experimental models are essential to precisely dissect the molecular mechanisms of disease and to devise effective therapeutic strategies. The most commonly used models are either in vitro or in vivo, and among the latter murine models are by far the most versatile and popular. Here, we critically revised the most relevant literature focused on the experimental models, providing an update on the mammalian models of CMT2A developed to date. We highlighted the different phenotypic, histopathological and molecular characteristics, and their use in translational studies for bringing potential therapies from the bench to the bedside. In addition, we discussed limitations of these models and perspectives for future improvement.

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Osteolineage depletion of mitofusin2 enhances cortical bone formation in female mice

Cited by 6 publications

References 46 publications

MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway

MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway

Ablation of Discoidin Domain Receptor 1 Provokes an Osteopenic Phenotype by Regulating Osteoblast/Osteocyte Autophagy and Apoptosis

Charcot–Marie‐Tooth type 2A in vivo models: Current updates

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