TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2

Li, Jinteng; Wang, Peng; Xie, Zhongyu; Wang, Shan; Cen, Shuizhong; Li, Ming; Liu, Wenjie; Tang, Simin; Ye, Guiwen; Zheng, Guoyan; Su, Huilan; Ma, Mengjun; Wu, Xiaohua; Wu, Yanfeng; Shen, Huiyong

doi:10.1038/s41418-019-0328-3

Cited by 41 publications

(45 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have demonstrated that the shift in preferential differentiation of MSCs from osteoblasts to adipocytes plays a role in the pathogenesis of osteoporosis via reducing bone mineral density [23]. We have already demonstrated that TRAF4 positively regulated the osteogenic differentiation of MSCs and TRAF4 was found to be abnormally decreased in osteoporosis specimen [14]. Thus, we hypothesis that TRAF4 not only regulate osteogenic differentiation of MSCs but also modulate the adipogenic capacity of MSCs.…”

Section: Introductionmentioning

confidence: 66%

“…reported that TRAF4 interacts with other proteins primarily through the RING domain or the TRAF domain [12,26]. Thus, we transfected plasmids encoding Myc-TRAF4 or deletion mutants (TRAF4 DRING or TRAF4 DTRAF) and Flag-PKM2 into 293T cells, which were then subjected to immunoprecipitation with an anti-Myc antibody and immunoblotting with an anti-Flag antibody.…”

Section: Traf4 Binds With Pkm2 Through the Ring Domain And N-and Ctermentioning

confidence: 99%

“…Previous animal studies have demonstrated that TRAF4 is required for embryogenesis and that TRAF4 deficiency can lead to serious skeletal malformation, which suggests that TRAF4 plays a critical role in bone development and metabolism [13]; however, the exact molecular mechanism requires further study. Our previous study demonstrated that TRAF4 positively regulates the osteogenic differentiation of MSCs by acting as an E3 ubiquitin ligase to degrade Smurf2 via the K48linked ubiquitination of Smurf2 [14]. Accumulating studies have revealed that the adipogenic-osteogenic balance plays a critical role in bone metabolism [15].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

Cen

Cai

et al. 2020

EBioMedicine

Self Cite

View full text Add to dashboard Cite

Background: Mesenchymal stem cells (MSCs) selectively differentiate into adipocytes or osteoblasts, and several molecules control the fate determination of MSCs. Understanding these key checkpoints greatly contributes to the ability to induce specific MSC differentiation for clinical applications. In this study, we aimed to explore whether TNF receptor-associated factor 4 (TRAF4) affects MSC adipogenic differentiation, which we previously reported that could positively regulated the osteogenic differentiation. Methods: Western blotting and Real-time Polymerase Chain Reaction were used to detected the expression pattern of TRAF4 during adipogenic differentiation. Lentivirus was constructed to regulate TRAF4 expression, and oil red O staining and Western blotting were used to assess its role in adipogenesis, which was confirmed in vivo by implanting an MSC-matrigel mixture into nude mice. Western blotting was used to detect the activated signaling pathways, and a specific inhibitor and agonist were used to clear the roles of the key signaling pathways. Additionaly, Co-Immunoprecipitation was conducted to find that Pyruvate kinase isozyme type M2 (PKM2) interacts with TRAF4, and to further explore their binding and functional domains. Finally, an RNA-binding protein immunoprecipitation assay and Western blotting were used to detect whether N6methyladenosine mediates the decreased TRAF4 expression during adipogenic differentiation. Findings: The results demonstrated that TRAF4 negatively regulates MSC adipogenesis in vitro and in vivo. Mechanistically, we revealed that TRAF4 binds to PKM2 to activate the kinase activity of PKM2, which subsequently activates b-catenin signaling and then inhibits adipogenesis. Furthermore, TRAF4 downregulation during adipogenesis is regulated by ALKBH5-mediated N6-methyladenosine RNA demethylation. Interpretation: TRAF4 negatively regulates the adipogenesis of MSCs by activating PKM2 kinase activity, which may act as a checkpoint to fine-tune the balance of adipo-osteogenic differentiation, and suggests that TRAF4 may be a novel target of MSCs in clinical use and may also illuminate the underlying mechanisms of bone metabolic diseases.

show abstract

Section: Introductionmentioning

confidence: 66%

Section: Traf4 Binds With Pkm2 Through the Ring Domain And N-and Ctermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

Cen

Cai

et al. 2020

EBioMedicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Fracture is very common in clinic, a rapid healing of fracture can help patient get early recovery, decrease the occurrence of certain related complications, as well as improving the quality of life. Osteoblast differentiation is vital during bone remodelling and fracture healing and is regulated by an array of biological factors . MC3T3‐E1 cells are precursors of osteoblasts, which are established from a C57BL/6 mouse calvaria and selected on the basis of high alkaline phosphatase (ALP) activity in the resting state .…”

Section: Introductionmentioning

confidence: 99%

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

Xiong

Yan

Chen

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Interleukin‐10 (IL‐10) displays well‐documented anti‐inflammatory effects, but its effects on osteoblast differentiation have not been investigated. In this study, we found IL‐10 negatively regulates microRNA‐7025‐5p (miR‐7025‐5p), the down‐regulation of which enhances osteoblast differentiation. Furthermore, through luciferase reporter assays, we found evidence that insulin‐like growth factor 1 receptor (IGF1R) is a miR‐7025‐5p target gene that positively regulates osteoblast differentiation. In vivo studies indicated that the pre‐injection of IL‐10 leads to increased bone formation, while agomiR‐7025‐5p injection delays fracture healing. Taken together, these results indicate that IL‐10 induces osteoblast differentiation via regulation of the miR‐7025‐5p/IGF1R axis. IL‐10 therefore represents a promising therapeutic strategy to promote fracture healing.

show abstract

“… 4 Accumulating evidence has suggested that induction of adipocyte differentiation impairs bone formation, while increased osteogenic differentiation is essential for bone mass increase. 5 , 6 , 7 Therefore, a clear understanding of MSC fate regulation is required. Recent studies have focused on investigating the regulation of extrinsic and intrinsic regulators on MSC fate.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Circulating miR-194-5p Reverses Osteoporosis through Wnt5a/β-Catenin-Dependent Induction of Osteogenic Differentiation

Yan

Xue

et al. 2020

Molecular Therapy - Nucleic Acids

View full text Add to dashboard Cite

Mesenchymal stem cells (MSCs) critically contribute to bone formation, and proper induction of osteogenic differentiation can lead to an increase in bone mass. In the present study, we reported that an increased miR-194-5p level in plasma is inversely related to the degree of bone formation in osteoporosis patients. We also noted that increased miR-194-5p in the MSCs of ovariectomized (OVX) mice and agomiR-194-5p manipulation of miR-194-5p significantly suppressed bone formation, both in aged and OVX mice. Furthermore, our in vitro study showed that overexpression of miR-194-5p suppresses osteogenic differentiation, as evidenced by the decreased bone formation marker genes and matrix mineralization. The luciferase assay indicated that Wnt family member 5a (Wnt5a) is a target gene of miR-194-5p that positively regulates osteogenic differentiation. Collectively, these data indicated that miR-194-5p inhibition may be a potential strategy for osteoporosis prevention.

show abstract

TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2

Cited by 41 publications

References 48 publications

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

TRAF4 acts as a fate checkpoint to regulate the adipogenic differentiation of MSCs by activating PKM2

IL‐10 induces MC3T3‐E1 cells differentiation towards osteoblastic fate in murine model

Inhibition of Circulating miR-194-5p Reverses Osteoporosis through Wnt5a/β-Catenin-Dependent Induction of Osteogenic Differentiation

Contact Info

Product

Resources

About