Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148

Shimazu, Junko; Wei, Jianwen; Karsenty, G.

doi:10.1016/j.celrep.2016.03.003

Cited by 59 publications

(44 citation statements)

References 30 publications

(45 reference statements)

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“…Recent study reports that AMPK phosphorylates Smurf1, the ubiquitin E3-ligase of Runx2, in osteoblast. 50 This phosphorylation blunts Smurf1's ubiquitin E3-ligase activity and thus promotes Runx2 expression in osteoblast. 50 However, we found silencing of Smurf1 could not alter Runx2 expression in VSMC (data not shown).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

Cai

Ding

Zhang

et al. 2016

Circulation Research

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Section: Discussionmentioning

confidence: 99%

“…50 This phosphorylation blunts Smurf1's ubiquitin E3-ligase activity and thus promotes Runx2 expression in osteoblast. 50 However, we found silencing of Smurf1 could not alter Runx2 expression in VSMC (data not shown). This might explain why the roles of AMPK in osteoblastic differentiation are opposite in VSMC and osteoblast.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

Cai

Ding

Zhang

et al. 2016

Circulation Research

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“…Since bone formation is a process subjected to strict regulation, once the Smad proteins have fulfilled their function, they are ubiquitinated by the HECT‐type ubiquitin ligase Smurf1 (Smad ubiquitination regulatory factor 1), and subsequently degraded by the ubiquitin‐proteasome system . Besides its direct implication in flagging the Smad proteins for destruction, Smurf1 seems to have an additional function leading to the suppression of bone formation, since this protein would prevent osteoblast differentiation by decreasing the accumulation of Runx2 in these cells, and their subsequent differentiation .…”

Section: Introductionmentioning

confidence: 99%

Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration

García-García

Ruiz

Reyes

et al. 2019

Stem Cells Translational Medicine

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Despite the great advance of bone tissue engineering in the last few years, repair of bone defects remains a major problem. Low cell engraftment and dose-dependent side effects linked to the concomitant administration of bone morphogenetic proteins (BMPs) are the main problems currently hindering the clinical use of mesenchymal stem cell (MSC)-based therapies in this field. We have managed to bypass these drawbacks by combining the silencing the Smurf1 ubiquitin ligase in MSCs with the use of a scaffold that sustainably releases low doses of BMP-2. In this system, Smurf1 silencing is achieved by using GapmeRs, a clinically safe method that avoids the use of viral vectors, facilitating its translation to the clinic. Here, we show that a single transient transfection with a small quantity of a Smurf1-specific GapmeR is able to induce a significant level of silencing of the target gene, enough to prime MSCs for osteogenic differentiation. Smurf1 silencing highly increases MSCs responsiveness to BMP-2, allowing a dramatic reduction of the dose needed to achieve the desired therapeutic effect. The combination of these primed cells with alginate scaffolds designed to sustainably and locally release low doses of BMP-2 to the defect microenvironment is able to induce the formation of a mature bone matrix both in an osteoporotic rat calvaria system and in a mouse ectopic model. Importantly, this approach also enhances osteogenic differentiation in MSCs from osteoporotic patients, characterized by a reduced bone-forming potential, even at low BMP doses, underscoring the regenerative potential of this system. STEM CELLS The need to administrate high doses of bone morphogenetic proteins (BMPs) to promote osteogenesis in certain orthopedic applications, along with their associated detrimental effects, is hindering the clinical use of tissue engineering techniques in this particular field. Silencing of the Smurf1 gene in mesenchymal stem cells (MSCs) by in situ transfecting these cells with an antisense oligonucleotide, a clinically safe approach, significantly increases the susceptibility of MSCs to BMP-2. The use of MSCs expressing low levels of Smurf1, together with biocompatible scaffolds that sustainably release low doses of BMP in a controlled manner, might be able to promote bone formation, avoiding the harmful effects linked to the presence of high concentration of BMPs in circulating blood.

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“…In addition, a pivotal role in colon, pancreatic, and breast cancer tumor progression has been reported for Smurf1 (33). Of note, recent studies have identified Smurf1 as a determinant of bone formation and glucose homeostasis postnatally and have demonstrated its functional role in metabolism (34,35); however, the physiologic roles that Smurf1 plays in the regulation of steroid-induced gonad function have been largely unveiled.…”

mentioning

confidence: 99%

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

Sun

Chu

et al. 2018

FASEB j.

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Testosterone is essential for spermatogenesis and the maintenance of secondary sexual characteristics in males. An important transcription factor, LIM-homeobox gene 9 (Lhx9) is indispensable for testis development and testosterone production; however, post-translational modifications of Lhx9 are largely unknown. Here, for the first time to our knowledge, we demonstrate that the level of Lhx9 protein increases in human chorionic gonadotropin-exposed Leydig cells and can be polyubiquitylated. We found that Smad ubiquitylation regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, targets Lhx9 for ubiquitin-mediated proteasome degradation, thereby negatively modulating its function. Increasing Smurf1 decreases the level of Lhx9 and inhibits the Lhx9 transactivation capacity of steroidogenic factor 1 [nuclear receptor subfamily 5, group A, member 1 (NR5A1)]. In contrast, the depletion of Smurf1 leads to increased expression of Lhx9 protein and enhances testosterone biosynthesis-related gene transcripts [NR5A1, steroidogenic acute regulatory protein, CYP17A1, hydroxy-δ-5-steroid dehydrogenase, hydroxy-δ-5-steroid dehydrogenase isomerase 6, and hydroxysteroid (17-β) dehydrogenase 3] and testosterone production in Leydig cells. Furthermore, we found that Smurf1 knockout mice exhibit higher levels of Lhx9 protein and steroidogenesis, which leads to increased serum testosterone concentration. These findings reveal that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly. Our results provide new insights into the molecular events that play a role in the homeostasis of testosterone levels and may provide a new target for testosterone regulation.-Hu, F., Zhu, Q., Sun, B., Cui, C., Li, C., Zhang, L. Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells.

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Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148

Cited by 59 publications

References 30 publications

Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

Ablation of Adenosine Monophosphate-Activated Protein Kinase α1 in Vascular Smooth Muscle Cells Promotes Diet-Induced Atherosclerotic Calcification In Vivo

Smurf1 Silencing Using a LNA-ASOs/Lipid Nanoparticle System to Promote Bone Regeneration

Smad ubiquitylation regulatory factor 1 promotes LIM‐homeobox gene 9 degradation and represses testosterone production in Leydig cells

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