Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation

Shin, Hye‐Rim; Islam, Rabia; Yoon, Won‐Joon; Lee, Taegyung; Cho, Young‐Dan; Bae, Hyun Cheol; Kim, Bongsu; Woo, Kyung Mi; Baek, Jeong‐Hwa; Ryoo, Hyun‐Mo

doi:10.1074/jbc.m115.698563

Cited by 23 publications

(34 citation statements)

References 57 publications

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“…Axin2, a key negative regulator in bone remodeling of adult mice, has been shown to regulate osteoblast differentiation through the β‐Catenin‐BMP2/4‐OSX signaling pathway in osteoblasts (Yan et al, ). In summary, the signal crosstalk data, the ultimate effect of Pin1‐mediated isomerization on Runx2 (Yoon et al, ), and the role of Pin1 as a stabilizer of R‐Smads and β‐catenin (Yoon et al, ; Shin et al, ) all support the idea that Pin1 is crucial for Runx2 expression and function. Thus, Pin1‐mediated regulation is a key component of bone development that acts on multiple levels.…”

Section: Role Of Pin1 In Osteoblast Cell Signalingmentioning

confidence: 83%

“…Induction of Wnt signaling is also known to stimulate autocrine Bmp‐2 expression (Cho et al, ) and to directly drive Runx2 activity (Gaur et al, ). Thus, Pin1‐mediated β‐catenin nuclear retention (Shen et al, ; Shin et al, ) and stabilization, together with R‐Smad stabilization, indirectly increase Runx2 activity. Furthermore, BMP‐2‐activated MAPK signaling pathways converge on Runx2 to regulate BMP‐2‐induced osteoblastic differentiation (Huang et al, ).…”

Section: Role Of Pin1 In Osteoblast Cell Signalingmentioning

confidence: 99%

“…The Wnt/b-catenin pathway has also been implicated in the bone cell response to mechanical stimuli. Moreover, Pin1 deficiency has been shown to reduce the level of nuclear b-catenin in bone lining cells (Shin et al, 2016), tumor cells (Ryo et al, 2001), and neuroprogenitors (Nakamura et al, 2012).…”

Section: Pin1 and Wnt Signalingmentioning

confidence: 99%

“…This finding triggered an array of studies focusing on the molecular role of Pin1 in bone cells. Later, Pin1 was found to be related to developmental defects (Yoon et al, 2013) and bone remodeling (Shen et al, 2013;Islam et al, 2014a;Yoon et al, 2015;Shin et al, 2016).…”

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confidence: 99%

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Pin1, the Master Orchestrator of Bone Cell Differentiation

Islam

Yoon

Ryoo

2017

Journal Cellular Physiology

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Pin1 is an enzyme that specifically recognizes the peptide bond between phosphorylated serine or threonine (pS/pT-P) and proline. This recognition causes a conformational change of its substrate, which further regulates downstream signaling. Pin1 mice show developmental bone defects and reduced mineralization. Pin1 targets RUNX2 (Runt-Related Transcription Factor 2), SMAD1/5, and β-catenin in the FGF, BMP, and WNT pathways, respectively. Pin1 has multiple roles in the crosstalk between different anabolic bone signaling pathways. For example, it controls different aspects of osteoblastogenesis and increases the transcriptional activity of Runx2, both directly and indirectly. Pin1 also influences osteoclastogenesis at different stages by targeting PU.1 (Purine-rich nucleic acid binding protein 1), C-FOS, and DC-STAMP. The phenotype of Pin1 mice has led to the recent identification of multiple roles of Pin1 in different molecular pathways in bone cells. These roles suggest that Pin1 can be utilized as an efficient drug target in congenital and acquired bone diseases. J. Cell. Physiol. 232: 2339-2347, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Role Of Pin1 In Osteoblast Cell Signalingmentioning

confidence: 83%

Section: Role Of Pin1 In Osteoblast Cell Signalingmentioning

confidence: 99%

Section: Pin1 and Wnt Signalingmentioning

confidence: 99%

mentioning

confidence: 99%

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Pin1, the Master Orchestrator of Bone Cell Differentiation

Islam

Yoon

Ryoo

2017

Journal Cellular Physiology

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“…*P < 0.05 vs the control group; # P < 0.05 vs the activin A and CHIR99021 groups; Data in the figure were measurement data, which were expressed as the mean ± standard deviation and compared by one-way ANOVA; the experiment was repeated three times in an independent manner. 31 The upregulated transcription factor Runx2 was reported to enhance osteoblast differentiation, the formation of the skeleton, as well as chondrocyte hypertrophy. Wnt consists of a large secretory glycoprotein family, which plays a major role in regulating multicellular organisms, such as cell proliferation, migration, differentiation, and polarity.…”

Section: Discussionmentioning

confidence: 99%

Wnt and BMP signaling pathways co‐operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2

Wei

Chen

et al. 2018

J of Cellular Biochemistry

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Osteoblast differentiation, defined as the process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, is directly linked to multiple myeloma (MM) bone disease. Wnt and bone morphogenetic protein (BMP) are proved to be implicated in the pathological or defective osteoblast differentiation process. This study aims to test the involvement of Wnt, bone morphogenetic proteins (BMP) pathways, and empty spiracles homeobox 2 (EMX2) in osteoblast differentiation and MM development. Initially, differentially expressed genes in bone marrow mesenchymal stem cells (MSCs) from MM patients and healthy donors were identified using microarray‐based gene expression profiling. The functional role of Wnt and BMP in MM was determined. Next, we focused on the co‐operative effects of Wnt and BMP on calcium deposition, alkaline phosphatase (ALP) activity, the number of mineralized nodules, and osteocalcin (OCN) content in MSCs. The expression patterns of Wnt and BMP pathway–related genes, EMX2 and osteoblast differentiation‐related factors were determined to assess their effects on osteoblast differentiation. Furthermore, regulation of Wnt and BMP in ectopic osteogenesis was also investigated in vivo. An integrated genomic screen suggested that Wnt and BMP regularly co‐operate to regulate EMX2 and affect MM. EMX2 was downregulated in MSCs. The activated Wnt and BMP resulted in more calcium salt deposits, mineralized nodules, and a noted increased in ALP activity and OCN content by upregulating EMX2, leading to induced differentiation of MSCs into osteoblasts. Collectively, this study demonstrated that Wnt and BMP pathways could co‐operatively stimulate differentiation of MSCs into osteoblasts and inhibit MM progression, representing potential targets for MM treatment.

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ACVR1‐knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice

Wang

Sun

Wang

et al. 2018

J of Cellular Biochemistry

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Osteogenic differentiation refers to the process of bone formation and remodeling, which is controlled by complex molecular mechanisms. Activin A receptor type I (ACVR1) is reported to be associated with osteogenic differentiation. However, the underlying molecular mechanism remains elusive. Therefore, this study evaluates the function of ACVR1 in osteogenic differentiation through the Wnt signaling pathway. The expression of osteocalcin (Oc) and osterix together with osteogenic differentiation and mineralization was examined in ACVR1‐knockout (KO) mouse. Furthermore, the Wnt signaling pathway was inhibited in bone marrow stromal cells (BMSCs) of mice to explore the role of the Wnt signaling pathway in osteogenic differentiation by means of alkaline phosphatase (ALP) activity detection and evaluation of mineralized nodules and calcium content. Subsequently, the effect of ACVR1 on the Wnt signaling pathway was assessed by determining the expression of ACVR1, β‐catenin, glycogen synthase kinase 3 β (GSK3β), dickkopf‐related protein 1 (DKK1), and frizzled class receptor 1 (FZD1). Both their effects on osteogenic differentiation were further evaluated by determination of Oc, osterix, and Runx2 expression. AVCR1 KO mice exhibited increased Oc and osterix expression and promoted bone resorption and formation. ACVR1‐knockout was observed to activate the Wnt signaling pathway with an increase of β‐catenin and reductions in GSK3β, DKK1, and FZD1. With the inhibited Wnt signaling pathway expression of Oc, osterix, and Runx2 was decreased, and ALP activity, mineralized nodule, and calcium content in cellular matrix were decreased as well, indicating that inactivation of the Wnt signaling pathway reduced the differentiation of BMSCs into osteoclasts. These findings indicate that ACVR1‐knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice.

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Pin1-mediated Modification Prolongs the Nuclear Retention of β-Catenin in Wnt3a-induced Osteoblast Differentiation

Cited by 23 publications

References 57 publications

Pin1, the Master Orchestrator of Bone Cell Differentiation

Pin1, the Master Orchestrator of Bone Cell Differentiation

Wnt and BMP signaling pathways co‐operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2

ACVR1‐knockout promotes osteogenic differentiation by activating the Wnt signaling pathway in mice

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