Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

Xiao, Zhousheng; Baudry, Jérôme; Cao, Li; Huang, Jinsong; Chen, Hao; Yates, Charles R.; Li, Wei; Dong, Bo; Waters, Christopher M.; Smith, Jeremy C.; Quarles, L. Darryl

doi:10.1172/jci93725

Cited by 60 publications

(88 citation statements)

References 72 publications

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“…TAZ has also been shown to suppress adipocyte differentiation by transcriptionally repressing PPARG-mediated gene expression (29,30). A recent study reports that polycystins and TAZ integrate at the molecular level to reciprocally regulate osteoblast and adipocyte differentiation (40). We found that Bmncr served as a scaffold to assembly of TAZ and ABL and activation of the TAZ and RUNX2 transcriptional complex.…”

Section: Discussionmentioning

confidence: 68%

“…TAZ, as a transcriptional coactivator for RUNX2-induced Bglap gene expression, is an important endogenous regulator of osteoblast differentiation (29,39,40). TAZ has also been shown to suppress adipocyte differentiation by transcriptionally repressing PPARG-mediated gene expression (29,30).…”

Section: Discussionmentioning

confidence: 99%

“…ANOVA was used to identify in BMSCs is an attractive topic for future study. In the study by Xiao (40), a compound termed Zinc01442821 was discovered to promote TAZ signaling through regulating PC1/TAZ interactions. Another interesting strategy is to deliver exogenous Bmncr or TAZ specifically into BMSCs using a rAAV delivery system.…”

Section: Discussionmentioning

confidence: 99%

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Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging

Li¹,

Xiao²,

Yang³

et al. 2018

Journal of Clinical Investigation

184

174

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Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-related lineage switch between osteogenic and adipogenic fates, which contributes to bone loss and adiposity. Here we identified a long noncoding RNA, Bmncr, which regulated the fate of BMSCs during aging. Mice depleted of Bmncr (Bmncr-KO) showed decreased bone mass and increased bone marrow adiposity, whereas transgenic overexpression of Bmncr (Bmncr-Tg) alleviated bone loss and bone marrow fat accumulation. Bmncr regulated the osteogenic niche of BMSCs by maintaining extracellular matrix protein fibromodulin (FMOD) and activation of the BMP2 pathway. Bmncr affected local 3D chromatin structure and transcription of Fmod. The absence of Fmod modified the bone phenotype of Bmncr-Tg mice. Further analysis revealed that Bmncr would serve as a scaffold to facilitate the interaction of TAZ and ABL, and thus facilitate the assembly of the TAZ and RUNX2/PPARG transcriptional complex, promoting osteogenesis and inhibiting adipogenesis. Adeno-associated viral-mediated overexpression of Taz in osteoprogenitors alleviated bone loss and marrow fat accumulation in Bmncr-KO mice. Furthermore, restoring BMNCR levels in human BMSCs reversed the age-related switch between osteoblast and adipocyte differentiation. Our findings indicate that Bmncr is a key regulator of the age-related osteogenic niche alteration and cell fate switch of BMSCs.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

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Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging

Li¹,

Xiao²,

Yang³

et al. 2018

Journal of Clinical Investigation

184

174

View full text Add to dashboard Cite

show abstract

“…Previous studies on mechanosensitive molecules demonstrated a molecular link between mechanical stimulation and bone‐specific transcription factor function such as Runx‐2 gene expression (Xiao et al, 2018). Runx‐2, the key nuclear protein regulating of osteoblastic differentiation and rate of bone formation, has been suggested to be involved in the bone's adaptive response to mechanical stimulation (Costessi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Song

Liu

et al. 2020

Cell Biology International

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Mechanically induced biological responses in bone cells involve a complex biophysical process. Although various mechanosensors have been identified, the precise mechanotransduction pathway remains poorly understood. PIEZO1 is a newly discovered mechanically activated ion channel in bone cells. This study aimed to explore the involvement of PIEZO1 in mechanical loading (fluid shear stress)‐induced signaling cascades that control osteogenesis. The results showed that fluid shear stress increased PIEZO1 expression in MC3T3‐E1 cells. The fluid shear stress elicited the key osteoblastic gene Runx‐2 expression; however, PIEZO1 silencing using small interference RNA blocked these effects. The AKT/GSK‐3β/β‐catenin pathway was activated in this process. PIEZO1 silencing impaired mechanically induced activation of the AKT/GSK‐3β/β‐catenin pathway. Therefore, the results demonstrated that MC3T3‐E1 osteoblasts required PIEZO1 to adapt to the external mechanical fluid shear stress, thereby inducing osteoblastic Runx‐2 gene expression, partly through the AKT/GSK‐3β/β‐catenin pathway.

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“…By accounting for the conformational diversity of the receptor ensemble docking enhances the likelihood of identifying predicted hits (enrichment), which may be lost when screening against a single conformation of the target 12 . We have previously applied this technique to derive experimentally-verified hits for several protein targets to treat diseases ranging from bacterial infections to osteoporosis [14][15][16][17][18][19][20][21][22] . For this work three phases of calculations were performed: structural modeling, molecular simulations (ensemble building), and small-molecule docking (in silico ligand screening)…”

Section: Methodsmentioning

confidence: 99%

Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

Smith

Smith²

2020

Preprint

Self Cite

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The novel Wuhan coronavirus (SARS-CoV-2) has been sequenced, and the virus shares substantial similarity with SARS-CoV. Here, using a computational model of the spike protein (S-protein) of SARS-CoV-2 interacting with the human ACE2 receptor, we make use of the world's most powerful supercomputer, SUMMIT, to enact an ensemble docking virtual high-throughput screening campaign and identify small-molecules which bind to either the isolated Viral S-protein at its host receptor region or to the S protein-human ACE2 interface. We hypothesize the identified small-molecules may be repurposed to limit viral recognition of host cells and/or disrupt host-virus interactions. A ranked list of compounds is given that can be tested experimentally.<br>

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Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

Cited by 60 publications

References 72 publications

Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging

Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging

Fluid shear stress induces Runx‐2 expression via upregulation of PIEZO1 in MC3T3‐E1 cells

Repurposing Therapeutics for COVID-19: Supercomputer-Based Docking to the SARS-CoV-2 Viral Spike Protein and Viral Spike Protein-Human ACE2 Interface

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