Targeting Pyk2 inhibition enhances bone restoration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1106770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28859419_1.fastq.gz | Fastqsanger.gz | |||
| SRR28859419_2.fastq.gz | Fastqsanger.gz | |||
| SRR28859420_1.fastq.gz | Fastqsanger.gz | |||
| SRR28859420_2.fastq.gz | Fastqsanger.gz | |||
| SRR28859421_1.fastq.gz | Fastqsanger.gz |
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Project description:Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. Using an ovariectomized mouse model, we administered Pyk2-Inh orally, resulting in increased bone mass characterized by reduced bone resorption, increased bone formation and decreased bone marrow fat. In vitro, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts. Additionally, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through an increase in canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cell into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies.
2024-11-27 | GSE266328 | GEO
Project description:Understanding the intricate cellular interactions involved in bone restoration is crucial for developing effective strategies to promote bone healing and mitigate conditions such as osteoporosis and fractures. Here, we provide compelling evidence supporting the anabolic effects of a pharmacological Pyk2 inhibitor (Pyk2-Inh) in promoting bone restoration. In vitro, Pyk2 signaling inhibition markedly enhances alkaline phosphatase (ALP) activity, a hallmark of osteoblast differentiation, through activation of canonical Wnt/β-catenin signaling. Notably, analysis of human mesenchymal stem cells through RNA-seq revealed a novel candidate, SCARA5, identified through Pyk2-Inh treatment. We demonstrate that Scara5 plays a crucial role in suppressing the differentiation from stromal cells into adipocytes, and accelerates lineage commitment to osteoblasts, establishing Scara5 as a negative regulator of bone formation. Additionally, Pyk2 inhibition significantly impedes osteoclast differentiation and bone resorption. In a co-culture system comprising osteoblasts and osteoclasts, Pyk2-Inh effectively suppressed osteoclast differentiation, accompanied by a substantial increase in the transcriptional expression of Tnfrsf11b and Csf1 in osteoblasts, highlighting a dual regulatory role in osteoblast-osteoclast crosstalk. In an ovariectomized mouse model of osteoporosis, oral administration of Pyk2-Inh significantly increased bone mass by simultaneously reducing bone resorption, promoting bone formation and decreasing bone marrow fat. These results suggest Pyk2 as a potential therapeutic target for both adipogenesis and osteogenesis in bone marrow. Our findings underscore the importance of Pyk2 signaling inhibition as a key regulator of bone remodeling, offering promising prospects for the development of novel osteoporosis therapies.
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Project description:Cancer stem cells (CSCs) are implicated in tumor initiation, metastasis and drug resistance, and are considered as attractive targets for cancer therapy. We identified a clinically relevant signaling nexus mediated by PYK2 and its impact on stemness in triple negative breast cancer (TNBC). PYK2 depletion in multiple mesenchymal TNBC cell lines markedly reduced the expression of PKCα and AXL proteins and reduced the number of mammosphere-forming cells and cells harboring CSCs characteristic markers. PYK2 and PKCα cooperate at a convergence point of multiple stemness-inducing pathways to regulate AXL levels and concomitantly the levels/activation of key transcription factors implicated in stemness including STAT3, TAZ, FRA1 and SMAD3 as well as the pluripotent transcription factors Nanog and Oct4, and in-turn affect their target genes. Targeting the AXL-PYK2-PKCα circuit could be a promising strategy to eliminate CSCs in TNBC and possibly overcome drug resistance.
2021-03-26 | GSE166609 | GEO
Project description:We demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2 null mice provide a model for understanding fear-related disorders.
2022-02-02 | GSE180598 | GEO
Project description:We demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2 null mice provide a model for understanding fear-related disorders.
2022-02-02 | GSE158606 | GEO
Project description:Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. Here we used different genetic mouse models and show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or both, markedly reduced the number of infiltrating tumor macrophages and concomitantly inhibited tumor angiogenesis and tumor growth. Strikingly, PYK2 depletion only in macrophages was sufficient to induce similar effects. These phenotypic changes were associated with reduced monocyte recruitment and a substantial decrease in tumor-associated macrophages (TAMs). Mechanistically, we show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibited Notch1 signaling and consequently reduced CCL2 secretion by breast cancer cells, and concurrently reduced the levels of CCR2, CXCR4, IL4R, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization and tumor angiogenesis. PYK2 expression is correlated with infiltrated macrophages in breast cancer patients, and its significant effects on macrophage infiltration and their pro-tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy.
2022-02-09 | GSE193168 | GEO
Project description:Targeting NAT10 enhances healthspan and lifespan in a mouse model of human accelerated aging syndrome.
2018-03-22 | E-MTAB-6578 | biostudies-arrayexpress
Project description:FTO degradation targeting enhances anti-tumor immunity
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Project description:Myeloma bone disease is a devastating complication of multiple myeloma (MM) and is caused by dysregulation of bone remodeling processes in the bone marrow microenvironment. Previous studies showed that microRNA-138 (miR-138) is a negative regulator of osteogenic differentiation of mesenchymal stromal cells (MSCs) and that inhibiting its function enhances bone formation in vitro. In this study, we explored the role of miR-138 in myeloma bone disease and evaluated the potential of systemically delivered locked nucleic acid (LNA)-modified anti-miR-138 oligonucleotides in suppressing myeloma bone disease. We showed that expression of miR-138 was significantly increased in MSCs from MM patients (MM-MSCs) and myeloma cells compared to those from healthy subjects. Furthermore, inhibition of miR-138 resulted in enhanced osteogenic differentiation of MM-MSCs in vitro and increased number of endosteal osteoblastic lineage cells (OBCs) and bone formation rate in mouse models of myeloma bone disease. RNA sequencing of the OBCs identified TRPS1 and SULF2 as potential miR-138 targets that were de-repressed in anti-miR-138 treated mice. In summary, these data indicate that inhibition of miR-138 enhances bone formation in MM and that pharmacological inhibition of miR-138 could represent a new therapeutic strategy for treatment of myeloma bone disease.
2018-06-01 | GSE111651 | GEO
Project description:Inhibition of microRNA-138 enhances bone formation in multiple myeloma bone marrow niche
| PRJNA437669 | ENA