MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway
X-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease’s aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.977347/full |
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| author | Alok Tripathi Alok Tripathi Aijaz A. John Deepak Kumar Deepak Kumar Saurabh Kumar Kaushal Saurabh Kumar Kaushal Devendra Pratap Singh Devendra Pratap Singh Nazim Husain Jayanta Sarkar Jayanta Sarkar Divya Singh Divya Singh |
| author_facet | Alok Tripathi Alok Tripathi Aijaz A. John Deepak Kumar Deepak Kumar Saurabh Kumar Kaushal Saurabh Kumar Kaushal Devendra Pratap Singh Devendra Pratap Singh Nazim Husain Jayanta Sarkar Jayanta Sarkar Divya Singh Divya Singh |
| author_sort | Alok Tripathi |
| collection | DOAJ |
| description | X-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease’s aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in osteoblast functions. MicroRNAs sequence analysis showed differentially regulated miRNAs in phex silenced osteoblast cells. In this article, we report miR-539-3p, an unidentified novel miRNA, in the functional regulation of osteoblast. MiR-539-3p overexpression impaired osteoblast differentiation. Target prediction algorithm and experimental confirmation by luciferase 3’ UTR reporter assay identified LRP-6 as a direct target of miR-539-3p. Over expression of miR-539-3p in osteoblasts down regulated Wnt/beta catenin signaling components and deteriorated trabecular microarchitecture leading to decreased bone formation in ovariectomized (Ovx) mice. Additionally, biochemical bone resorption markers like CTx and Trap-5b were elevated in serum samples of mimic treated group, while, reverse effect was observed in anti-miR treated animals along with increased bone formation marker P1NP. Moreover, transcriptome analysis with miR-539-3p identified a novel uncharacterized Akap-3 gene in osteoblast cells, knock down of which resulted in downregulation of osteoblast differentiation markers at both transcriptional and translational level. Overall, our study for the first time reported the role of miR-539-3p in osteoblast functions and its downstream Akap-3 signalling in regulation of osteoblastogenesis. |
| first_indexed | 2024-04-12T10:24:20Z |
| format | Article |
| id | doaj.art-ea445b6bb6fd42e29b3272f09bfcaa45 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-12T10:24:20Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-ea445b6bb6fd42e29b3272f09bfcaa452022-12-22T03:37:00ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-09-011310.3389/fendo.2022.977347977347MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathwayAlok Tripathi0Alok Tripathi1Aijaz A. John2Deepak Kumar3Deepak Kumar4Saurabh Kumar Kaushal5Saurabh Kumar Kaushal6Devendra Pratap Singh7Devendra Pratap Singh8Nazim Husain9Jayanta Sarkar10Jayanta Sarkar11Divya Singh12Divya Singh13Division of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaDivision of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaDivision of Cancer Biology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaDivision of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaDivision of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaDivision of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaDivision of Cancer Biology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaDivision of Endocrinology, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, IndiaAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, IndiaX-linked hypophosphatemia (XLH), an inheritable form of rickets is caused due to mutation in Phex gene. Several factors are linked to the disease’s aetiology, including non-coding RNA molecules (miRNAs), which are key post-transcriptional regulators of gene expression and play a significant role in osteoblast functions. MicroRNAs sequence analysis showed differentially regulated miRNAs in phex silenced osteoblast cells. In this article, we report miR-539-3p, an unidentified novel miRNA, in the functional regulation of osteoblast. MiR-539-3p overexpression impaired osteoblast differentiation. Target prediction algorithm and experimental confirmation by luciferase 3’ UTR reporter assay identified LRP-6 as a direct target of miR-539-3p. Over expression of miR-539-3p in osteoblasts down regulated Wnt/beta catenin signaling components and deteriorated trabecular microarchitecture leading to decreased bone formation in ovariectomized (Ovx) mice. Additionally, biochemical bone resorption markers like CTx and Trap-5b were elevated in serum samples of mimic treated group, while, reverse effect was observed in anti-miR treated animals along with increased bone formation marker P1NP. Moreover, transcriptome analysis with miR-539-3p identified a novel uncharacterized Akap-3 gene in osteoblast cells, knock down of which resulted in downregulation of osteoblast differentiation markers at both transcriptional and translational level. Overall, our study for the first time reported the role of miR-539-3p in osteoblast functions and its downstream Akap-3 signalling in regulation of osteoblastogenesis.https://www.frontiersin.org/articles/10.3389/fendo.2022.977347/fullmicroRNAX-linked hypophosphatemiaPHEXLRP-6AKAP-3 |
| spellingShingle | Alok Tripathi Alok Tripathi Aijaz A. John Deepak Kumar Deepak Kumar Saurabh Kumar Kaushal Saurabh Kumar Kaushal Devendra Pratap Singh Devendra Pratap Singh Nazim Husain Jayanta Sarkar Jayanta Sarkar Divya Singh Divya Singh MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway Frontiers in Endocrinology microRNA X-linked hypophosphatemia PHEX LRP-6 AKAP-3 |
| title | MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway |
| title_full | MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway |
| title_fullStr | MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway |
| title_full_unstemmed | MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway |
| title_short | MiR-539-3p impairs osteogenesis by suppressing Wnt interaction with LRP-6 co-receptor and subsequent inhibition of Akap-3 signaling pathway |
| title_sort | mir 539 3p impairs osteogenesis by suppressing wnt interaction with lrp 6 co receptor and subsequent inhibition of akap 3 signaling pathway |
| topic | microRNA X-linked hypophosphatemia PHEX LRP-6 AKAP-3 |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.977347/full |
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