A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Kushioka, Junichi; Kaito, Takashi; Okada, Rintaro; Ishiguro, Hiroyuki; Bal, Zeynep; Kodama, Joe; Chijimatsu, Ryota; Pye, Melanie; Narimatsu, Masahiro; Wrana, Jeffrey L.; Inoue, Yasumichi; Ninomiya, Hirokazu; Yamamoto, Shin; Saitou, Takashi; Yoshikawa, Hideki; Imamura, Takeshi

doi:10.1038/s41413-020-00115-z

Cited by 28 publications

(27 citation statements)

References 45 publications

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“…Nedd4 exerts its molecular function mainly by ubiquitinating its substrates 39 , 40 . Ubiquitination of osteogenic-related proteins is closely related to bone growth and remodeling 41 , 42 . Zou et al reported that the E3 ubiquitin ligase WWP2 regulates craniofacial development through mono-ubiquitylation of goosecoid 43 .…”

Section: Discussionmentioning

confidence: 99%

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

Zheng

Zhou

et al. 2021

Cell Death Dis

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Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K–AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53–Nedd4–Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

Zheng

Zhou

et al. 2021

Cell Death Dis

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“…In addition to Smurf1, Smurf2 has been shown to negatively regulate BMP/Smad signaling via ubiquitination of Smad3 (Kushioka et al, 2020). In Xenopus embryos, Smurf2 also targets Smad1 for ubiquitination, similar to, but independent of, Smurf1 (Zhang et al, 2001).…”

Section: Bmp Signalingmentioning

confidence: 99%

E3 Ubiquitin Ligase-Mediated Regulation of Osteoblast Differentiation and Bone Formation

Shen

et al. 2021

Front. Cell Dev. Biol.

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The ubiquitin–proteasome system (UPS) is an essential pathway that regulates the homeostasis and function of intracellular proteins and is a crucial protein-degradation system in osteoblast differentiation and bone formation. Abnormal regulation of ubiquitination leads to osteoblast differentiation disorders, interfering with bone formation and ultimately leading to osteoporosis. E3 ubiquitin ligases (E3) promote addition of a ubiquitin moiety to substrate proteins, specifically recognizing the substrate and modulating tyrosine kinase receptors, signaling proteins, and transcription factors involved in the regulation of osteoblast proliferation, differentiation, survival, and bone formation. In this review, we summarize current progress in the understanding of the function and regulatory effects of E3 ligases on the transcription factors and signaling pathways that regulate osteoblast differentiation and bone formation. A deep understanding of E3 ligase-mediated regulation of osteoblast differentiation provides a scientific rationale for the discovery and development of novel E3-targeting therapeutic strategies for osteoporosis.

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“…TGF- β signaling targeting COL5A1 shows osteogenic potential by treatments in vitro and in vivo. It also has found that the TGF- β response element (T β RE) exists in the upstream of the Col1α1 transcription start site in mice, and it could activate Col1α with the assistance of various receptor complexes, such as Smad2/Smad3/Smad4 [ 68 , 69 ]. And Smad7 inhibits the activity of the Smad2/Smad3/Smad4 complex ( Figure 4 ).…”

Section: Regulatory Factors With Circadian Rhythms In Bone Ecmmentioning

confidence: 99%

Spatial-Temporal Patterns and Inflammatory Factors of Bone Matrix Remodeling

Wang

Guo

Chen

et al. 2021

Stem Cells International

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The bone extracellular matrix (ECM) contains organic and mineral constituents. The establishment and degradation processes of ECM connect with spatial and temporal patterns, especially circadian rhythms in ECM. These patterns are responsible for the physical and biological characteristics of bone. The disturbances of the patterns disrupt bone matrix remodeling and cause diverse bone diseases, such as osteogenesis imperfecta (OI) and bone fracture. In addition, the main regulatory factors and inflammatory factors also follow circadian rhythms. Studies show that the circadian oscillations of these factors in bone ECM potentially influence the interactions between immune responses and bone formation. More importantly, mesenchymal stem cells (MSCs) within the specific microenvironments provide the regenerative potential for tissue remodeling. In this review, we summarize the advanced ECM spatial characteristics and the periodic patterns of bone ECM. Importantly, we focus on the intrinsic connections between the immunoinflammatory system and bone formation according to circadian rhythms of regulatory factors in bone ECM. And our research group emphasizes the multipotency of MSCs with their microenvironments. The advanced understandings of bone ECM formation patterns and MSCs contribute to providing optimal prevention and treatment strategies.

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A novel negative regulatory mechanism of Smurf2 in BMP/Smad signaling in bone

Cited by 28 publications

References 45 publications

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

Beraprost ameliorates postmenopausal osteoporosis by regulating Nedd4-induced Runx2 ubiquitination

E3 Ubiquitin Ligase-Mediated Regulation of Osteoblast Differentiation and Bone Formation

Spatial-Temporal Patterns and Inflammatory Factors of Bone Matrix Remodeling

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