DEPTOR exacerbates bone–fat imbalance in osteoporosis by transcriptionally modulating BMSC differentiation

Ouyang, Zhicong; Kang, Dawei; Li, Kai; Liang, Guojun; Liu, Zezheng; Mai, Qiguang; Chen, Qingjing; Yao, Chenfeng; Wei, Ruiming; Tan, Xianjun; Bai, Xiaochun; Huang, Bin; Li, Qingchu

doi:10.1016/j.biopha.2022.113164

Cited by 13 publications

(6 citation statements)

References 47 publications

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Section: Discussionmentioning

confidence: 85%

“…While in the process of publishing our findings, Ouyang, et al demonstrated that knockout of DEPTOR in mice using Prx-Cre resulted in decreased accumulation of fat in bone after ovariectomy ( Ouyang et al, 2022 ). They also showed that DEPTOR interaction with TAZ was responsible for the phenotype observed ( Ouyang et al, 2022 ). Our work complements these previous findings showing that dysregulation of DEPTOR levels in humans due to two different mutations in the PTH/PTHrP receptor, PTH1R, also result in aberrant differentiation of skeletal progenitors leading to accumulation of fat or cartilage in the bones of patients with JMC and BOCD.…”

Section: Discussionmentioning

confidence: 85%

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Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

Csukasi

Bosakova

Bárta

et al. 2023

Front. Cell Dev. Biol.

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Alterations in the balance between skeletogenesis and adipogenesis is a pathogenic feature in multiple skeletal disorders. Clinically, enhanced bone marrow adiposity in bones impairs mobility and increases fracture risk, reducing the quality of life of patients. The molecular mechanism that underlies the balance between skeletogenesis and adipogenesis is not completely understood but alterations in skeletal progenitor cells’ differentiation pathway plays a key role. We recently demonstrated that parathyroid hormone (PTH)/PTH-related peptide (PTHrP) control the levels of DEPTOR, an inhibitor of the mechanistic target of rapamycin (mTOR), and that DEPTOR levels are altered in different skeletal diseases. Here, we show that mutations in the PTH receptor-1 (PTH1R) alter the differentiation of skeletal progenitors in two different skeletal genetic disorders and lead to accumulation of fat or cartilage in bones. Mechanistically, DEPTOR controls the subcellular localization of TAZ (transcriptional co-activator with a PDZ-binding domain), a transcriptional regulator that governs skeletal stem cells differentiation into either bone and fat. We show that DEPTOR regulation of TAZ localization is achieved through the control of Dishevelled2 (DVL2) phosphorylation. Depending on nutrient availability, DEPTOR directly interacts with PTH1R to regulate PTH/PTHrP signaling or it forms a complex with TAZ, to prevent its translocation to the nucleus and therefore inhibit its transcriptional activity. Our data point DEPTOR as a key molecule in skeletal progenitor differentiation; its dysregulation under pathologic conditions results in aberrant bone/fat balance.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

Csukasi

Bosakova

Bárta

et al. 2023

Front. Cell Dev. Biol.

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“…It is upregulated in adipogenic induction and downregulated in osteogenic induction of MP in vitro; it is upregulated in MP from ovariectomy-induced osteoporotic mice, in vivo. In contrast, targeted knockdown of Deptor in MP with Prrx1-Cre in mice with osteoporosis promote MP osteogenesis and inhibits adipogenesis to alleviate bone loss and bone marrow fat accumulation after OVX [ 126 ].…”

Section: Mps Respond To Skeletal Injurymentioning

confidence: 99%

The emerging studies on mesenchymal progenitors in the long bone

Shen

Huang

et al. 2023

Cell Biosci

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Mesenchymal progenitors (MPs) are considered to play vital roles in bone development, growth, bone turnover, and repair. In recent years, benefiting from advanced approaches such as single-cell sequence, lineage tracing, flow cytometry, and transplantation, multiple MPs are identified and characterized in several locations of bone, including perichondrium, growth plate, periosteum, endosteum, trabecular bone, and stromal compartment. However, although great discoveries about skeletal stem cells (SSCs) and progenitors are present, it is still largely obscure how the varied landscape of MPs from different residing sites diversely contribute to the further differentiation of osteoblasts, osteocytes, chondrocytes, and other stromal cells in their respective destiny sites during development and regeneration. Here we discuss recent findings on MPs’ origin, differentiation, and maintenance during long bone development and homeostasis, providing clues and models of how the MPs contribute to bone development and repair.

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“…Runx2 regulates the transcription of numerous genes and induces differentiation of BMSCs into osteoblasts. This mechanism is a necessary and sufficient condition for the differentiation of BMSCs into the osteoblast lineage and is important in the development of the skeletal system and bone metabolism (57)(58)(59)(60). Numerous studies have established that lncRNA upregulates BMSC osteogenic differentiation by acting as an miRNA sponge, which inhibits miRNA via competitive binding to miRNA; ultimately, this forms a lncRNA-miRNA network that upregulates Runx2 expression.…”

Section: Lncrna-mirna Network Regulation Promotes Osteogenic Differen...mentioning

confidence: 99%

Research progress on the role of lncRNA–miRNA networks in regulating adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporosis

Wang

et al. 2023

Front. Endocrinol.

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Osteoporosis (OP) is characterized by a decrease in osteoblasts and an increase in adipocytes in the bone marrow compartment, alongside abnormal bone/fat differentiation, which ultimately results in imbalanced bone homeostasis. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts and adipocytes to maintain bone homeostasis. Several studies have shown that lncRNAs are competitive endogenous RNAs that form a lncRNA–miRNA network by targeting miRNA for the regulation of bone/fat differentiation in BMSCs; this mechanism is closely related to the corresponding treatment of OP and is important in the development of novel OP-targeted therapies. However, by reviewing the current literature, it became clear that there are limited summaries discussing the effects of the lncRNA–miRNA network on osteogenic/adipogenic differentiation in BMSCs. Therefore, this article provides a review of the current literature to explore the impact of the lncRNA–miRNA network on the osteogenic/adipogenic differentiation of BMSCs, with the aim of providing a new theoretical basis for the treatment of OP.

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DEPTOR exacerbates bone–fat imbalance in osteoporosis by transcriptionally modulating BMSC differentiation

Cited by 13 publications

References 47 publications

Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

Skeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTOR

The emerging studies on mesenchymal progenitors in the long bone

Research progress on the role of lncRNA–miRNA networks in regulating adipogenic and osteogenic differentiation of bone marrow mesenchymal stem cells in osteoporosis

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