Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

Mukai, Tomoyuki; Fujita, Shunichi; Morita, Yoshitaka

doi:10.3390/cells8020195

Cited by 24 publications

(35 citation statements)

References 92 publications

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“…ous studies have reported that Tankyrase inhibition upregulate SH3BP2 1,4 , thus we examined gene expression of SH3BP2 in hBMSCs. Treatment with XAV-939 (3 µM) induced a significant upregulation in SH3BP2 gene…”

Section: Xav-939 Promoted Osteoblast Differentiation Of Hmscs Via Accmentioning

confidence: 99%

“…Tankyrase is part of poly (ADP-ribose) polymerase (PARPs) superfamily of 17 physiological human PARPs required for numerous cellular and molecular processes 1 – 3 including glucose metabolism, mitosis 4 , DNA damage repair 5 , genome stability 6 , cellular stress signaling 7 , signal transduction 6 , gene transcription 8 , telomere maintenance, and Wnt signaling 3 . Tankyrases are also promising drug targets that may be useful in several diseases affecting multiple organs 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

“…The two tankyrase proteins, Tankyrase-1 and tankyrase-2, also called PARP5a and PARP5b, respectively, are members of the PARP family 3 , 4 , 11 . Structurally, both tankyrase proteins comprise ankyrin repeats, a sterile alpha module, and a carboxy-terminal PARP catalytic domain with an additional N-terminal HPS domain in Tankyrase-1 3 , 4 , 11 . Tankyrase inhibition negatively regulates Wnt pathway 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

“…Tankyrases are also promising drug targets that may be useful in several diseases affecting multiple organs 9,10 . The two tankyrase proteins, Tankyrase-1 and tankyrase-2, also called PARP5a and PARP5b, respectively, are members of the PARP family 3,4,11 . Structurally, both tankyrase proteins comprise ankyrin repeats, a sterile alpha module, and a carboxy-terminal PARP catalytic domain with an additional N-terminal HPS domain in Tankyrase-1 3,4,11 .…”

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confidence: 99%

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Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

Almasoud

Binhamdan

Younis

et al. 2020

Sci Rep

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Tankyrase is part of poly (ADP-ribose) polymerase superfamily required for numerous cellular and molecular processes. Tankyrase inhibition negatively regulates Wnt pathway. Thus, Tankyrase inhibitors have been extensively investigated for the treatment of clinical conditions associated with activated Wnt signaling such as cancer and fibrotic diseases. Moreover, Tankyrase inhibition has been recently reported to upregulate osteogenesis through the accumulation of SH3 domain-binding protein 2, an adaptor protein required for bone metabolism. In this study, we investigated the effect of Tankyrase inhibition in osteoblast differentiation of human skeletal (mesenchymal) stem cells (hMSCs). A Tankyrase inhibitor, XAV-939, identified during a functional library screening of small molecules. Alkaline phosphatase activity and Alizarin red staining were employed as markers for osteoblastic differentiation and in vitro mineralized matrix formation, respectively. Global gene expression profiling was performed using the Agilent microarray platform. XAV-939, a Tankyrase inhibitor, enhanced osteoblast differentiation of hBMSCs as evidenced by increased ALP activity, in vitro mineralized matrix formation, and upregulation of osteoblast-related gene expression. Global gene expression profiling of XAV-939-treated cells identified 847 upregulated and 614 downregulated mRNA transcripts, compared to vehicle-treated control cells. It also points towards possible changes in multiple signaling pathways, including TGFβ, insulin signaling, focal adhesion, estrogen metabolism, oxidative stress, RANK-RANKL (receptor activator of nuclear factor κB ligand) signaling, Vitamin D synthesis, IL6, and cytokines and inflammatory responses. Further bioinformatic analysis, employing Ingenuity Pathway Analysis identified significant enrichment in XAV-939-treated cells of functional categories and networks involved in TNF, NFκB, and STAT signaling. We identified a Tankyrase inhibitor (XAV-939) as a powerful enhancer of osteoblastic differentiation of hBMSC that may be useful as a therapeutic option for treating conditions associated with low bone formation.

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Section: Xav-939 Promoted Osteoblast Differentiation Of Hmscs Via Accmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

Almasoud

Binhamdan

Younis

et al. 2020

Sci Rep

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“…From this standpoint, tankyrase can be a therapeutic target to modulate SH3BP2 protein expression. Tankyrase is a poly(ADP-ribose) polymerase that directly binds to SH3BP2 protein and subsequently mediates its degradation [22,42]. Increased tankyrase activity decreases SH3BP2 protein levels.…”

Section: Discussionmentioning

confidence: 99%

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

Kawahara

Mukai

Iseki

et al. 2020

Preprint

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Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways, including Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model.Methods: For the lupus model, we used Faslpr/lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody and rheumatoid factor, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice.Conclusions: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cell differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

Bai,

Yang,

Jia

et al. 2024

Medicinal Research Reviews

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Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long‐term medication‐induced drug resistance. Poly(ADP‐ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP‐DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first‐line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure–activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.

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Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2

Cited by 24 publications

References 92 publications

Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

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