CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

Chen, Po Chun; Liu, Ju-Fang; Fong, Yi Chin; Huang, Yuan; Chao, Chia Chia; Tang, Chih Hsin

doi:10.3390/ijms20133300

Cited by 30 publications

(25 citation statements)

References 42 publications

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“…However, PSMC6 gene knockout increased the phosphorylation level of PI3K compared with that of 8th week group (Figure 3g). These results suggested that activated PI3K/AKT signaling pathways can reduce apoptosis of osteoporosis‐induced osteoblasts and increase bone mineral density, which is consistent with the above reports (Chen et al, 2019). However, animal experimental studies are not sufficient to reveal the specific mechanism of PSMC6 in ovariectomy‐induced osteoporosis, we would use in vitro experiments to further validate the specific mechanism of PSMC6 in ovariectomy‐induced osteoporosis.…”

Section: Discussionsupporting

confidence: 92%

PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy‐induced osteoporosis mouse model

Zhang

Cao

et al. 2020

Journal Cellular Physiology

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There is now increasing evidence which suggests a key role for osteoblast apoptosis in the pathogenesis of postmenopausal osteoporosis. Here, we evaluated the role and mechanism of proteasome 26S subunit, ATPase (PSMC) 6, a protein that is highly expressed in bone. Gene expression pattern had been extracted based on database of Gene Expression Omnibus (GEO). GEO2R was employed for analyses, while the DAVID database was adopted to further analyze the gene ontology (GO) as well as Kyoto Encyclopedia of Genomes pathway (KEGG) enrichment. Then, the Search Tool Retrieval of Interacting Genes (STRING) was utilized to carry out interaction regulatory network for the top 200 differentially expressed genes (DEGs). A key gene, called PSMC6, was identified by Cytoscape 3.6.0. The OVX osteoporosis model was established in female C57BL/6 mice by full bilateral ovariectomy. According to our findings, PSMC6 gene knockout would elevate bone mineral density (BMD) and the phosphorylation level of PI3K protein and increased the protein level of cleaved caspase‐3/‐9 in OVX osteoporosis mice. Further, MTT, bromodeoxyuridine, and flow cytometry assays revealed that PSMC6 inhibition promoted the progression of cell cycle and cell proliferation, whereas, PSMC6 overexpression promoted the apoptosis and inhibited cell cycle progression and cell proliferation in vitro. Besides, we found that PI3K activation significantly decreased PSMC6‐induced osteoblast apoptosis and promoted cell proliferation through regulating the protein levels of p53, cyclinD1, and cleaved caspase‐3/9. In conclusion, PSMC6 aggravated the degree of OVX‐induced osteoporosis by inhibiting the PI3K/AKT signal transduction pathway, thereby promoting the apoptosis of osteoblasts.

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Section: Discussionsupporting

confidence: 92%

PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy‐induced osteoporosis mouse model

Zhang

Cao

et al. 2020

Journal Cellular Physiology

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“…Since CCN3 is known to promote BMP expression and bone formation, 13,14 to examine whether CCN3 is critical factor in prostate cancer CM, the prostate cancer CM was treated with CCN3 antibody. The results showed that CCN3 antibody effectively reduced prostate cancer CM‐promoted increases in BMP, Runx2 and osterix synthesis (Figure 2), indicating that prostate cancer‐derived CCN3 promotes the production of osteogenic factors in osteoblasts.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous research indicated that CCN3 promotes BMP‐4 production and bone mineralization in osteoblasts 13 . We have also shown that CCN3 enhances osteoblastic differentiation by upregulating Runx2 and osterix, and by inhibiting miR‐608 expression 14 . Conversely, CCN3 reportedly controls prostate osteolytic bone metastasis through RANKL‐dependent osteoclastogenesis 15 .…”

Section: Introductionmentioning

confidence: 96%

Prostate cancer‐secreted CCN3 uses the GSK3β and β‐catenin pathways to enhance osteogenic factor levels in osteoblasts

Chen¹,

Liu

Lin

et al. 2020

Environmental Toxicology

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Prostate cancer osteoblastic bone metastases are incurable and associated with chronic bone pain and a high mortality rate. Osteoclast‐targeting drugs intended to prevent skeletal‐related events associated with prostate cancer bone metastases do not prolong overall survival. Improved understanding of the bone‐derived factors that contribute to prostate cancer osteoblastic bone metastases is required to design treatments that will improve morbidities and overall survival. Activated osteoblasts stimulate prostate cancer growth in bone. In this study, we report that prostate cancer conditioned medium (CM) promoted bone morphogenetic protein (BMP)‐2, ‐4 and ‐7 production and the expression of osteogenic transcription factors Runx2 and osterix in osteoblasts. Treating the prostate cancer CM with antibody against CCN3 (nephroblastoma‐overexpressed), a cysteine‐rich protein that belongs to the CCN family, reduced all of these increases. Incubation of osteoblasts with CCN3 facilitated phosphorylation of GSK3β and β‐catenin. GSK3β and β‐catenin inhibitors or siRNAs all abolished CCN3‐induced promotion of BMPs, Runx2 and osterix expression in osteoblasts. Our results indicate that prostate cancer‐secreted CCN3 enhances BMP, Runx2 and osterix expression in osteoblasts via the GSK3β and β‐catenin signaling pathways. This understanding of the role played by CCN3 in osteoblastic prostate bone metastasis may lead to more efficient targeted therapies.

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“…AKT can also affect osteoblast survival and bone formation by retaining the Forkhead box protein O (FOXOs) in the cytoplasm [ 30 ]. Recent studies have shown that the PI3K/AKT pathway activation up-regulates the osteogenic differentiation markers gene expression, such as BMP2 and ALP, thus stimulating osteoblast differentiation and proliferation [ 31 ]. In contrast, the inhibition of PI3K/AKT signaling activity weakens the bone resportion capacity of osteoclasts [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Silencing of miR-483-5p alleviates postmenopausal osteoporosis by targeting SATB2 and PI3K/AKT pathway

Zhao

Ouyang

et al. 2021

Aging

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Postmenopausal osteoporosis (PMOP) poses a significant threat to women’s health worldwide. However, detailed molecular mechanism and therapeutic strategy for PMOP remain insufficient. Accumulating evidence suggests that miR-48-5p is implicated in the pathogenesis of osteoporosis. The present study aimed to determine the role and mechanism of miR-483-5p in PMOP. Results from PMOP patients demonstrated that miR-483-5p was up-regulated and SATB2 was down-regulated. Luciferase reporter assay identified SATB2 as a direct target gene of miR-483-5p. Experiments in MC3T3-E1 cells indicated that miR-483-5p mimic markedly inhibited cell viability as well as the expressions of OPG, RUNX2 and BMP2. And miR-483-5p inhibitor, SATB2-overexpressed lentiviruses (Lv-SATB2) or LY294002 (PI3K/AKT inhibitor) significantly reversed the above results. Similarly, PI3K/AKT signaling was activated by miR-483-5p mimic, and was inhibited in miR-483-5p inhibitor, Lv-SATB2 or LY294002 treated cells. In vivo experiments showed that miR-483-5p inhibitor significantly increased the bone mineral density and biomechanical parameters of femurs in ovariectomized (OVX) rats by targeting SATB2. In addition, the osteogenic differentiation and PI3K/AKT signaling were also regulated by miR-483-5p-SATB2 axis. Taken together, our findings indicated that miR-483-5p contributed to the pathogenesis of PMOP by inhibiting SATB2 and activating PI3K/AKT pathway. MiR-483-5p/SATB2 could be selected as a potential therapeutic target for PMOP.

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CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

Cited by 30 publications

References 42 publications

PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy‐induced osteoporosis mouse model

PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy‐induced osteoporosis mouse model

Prostate cancer‐secreted CCN3 uses the GSK3β and β‐catenin pathways to enhance osteogenic factor levels in osteoblasts

Silencing of miR-483-5p alleviates postmenopausal osteoporosis by targeting SATB2 and PI3K/AKT pathway

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