MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells
Mechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-10-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.747057/full |
| _version_ | 1819144039918731264 |
|---|---|
| author | Svitlana Melnik Nina Hofmann Jessica Gabler Nicole Hecht Wiltrud Richter |
| author_facet | Svitlana Melnik Nina Hofmann Jessica Gabler Nicole Hecht Wiltrud Richter |
| author_sort | Svitlana Melnik |
| collection | DOAJ |
| description | Mechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondrogenic differentiation potential. However, MSC-derived chondrocytes undergo hypertrophic degeneration that impedes their clinical application for cartilage regeneration. In our previous study, we established that several microRNAs (miRs) are differentially expressed between articular chondrocytes (AC) – and MSC-derived neocartilage, with miR-181a being the most prominent candidate as key microRNA involved in the regulation of a balance between chondral and endochondral differentiation. The aim of this study was the identification of precise mRNA targets and signaling pathways regulated by miR-181a in MSC during chondrogenesis. MiR-181a was upregulated during chondrogenesis of MSC, along with an increase of the hypertrophic phenotype in resulting cartilaginous tissue. By in silico analysis combined with miR reporter assay, the WNT signaling activator and BMP signaling repressor RSPO2 was suggested as a target of miR-181a. Further validation experiments confirmed that miR-181a targets RSPO2 mRNA in MSC. It was found that in human MSC miR-181a activated BMP signaling manifested by the accumulation of SOX9 protein and increased phosphorylation of SMAD1/5/9. These effects, together with the concomitant reduction of canonical WNT signaling induced by miR-181a mimic, were in accordance with the effects expected by the loss of RSPO2, thus indicating the causative link between miR-181a and RSPO2. Moreover, we observed that a tight correlation between miR-181a and miR-218 expression levels in healthy human cartilage tissue was disrupted in osteoarthritis (OA) highlighting the importance of the WNT-BMP signaling crosstalk for preventing OA. |
| first_indexed | 2024-12-22T12:35:48Z |
| format | Article |
| id | doaj.art-f219c9526da14ec59d8a54583763b1b2 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T12:35:48Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-f219c9526da14ec59d8a54583763b1b22022-12-21T18:25:35ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-10-01910.3389/fcell.2021.747057747057MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal CellsSvitlana MelnikNina HofmannJessica GablerNicole HechtWiltrud RichterMechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondrogenic differentiation potential. However, MSC-derived chondrocytes undergo hypertrophic degeneration that impedes their clinical application for cartilage regeneration. In our previous study, we established that several microRNAs (miRs) are differentially expressed between articular chondrocytes (AC) – and MSC-derived neocartilage, with miR-181a being the most prominent candidate as key microRNA involved in the regulation of a balance between chondral and endochondral differentiation. The aim of this study was the identification of precise mRNA targets and signaling pathways regulated by miR-181a in MSC during chondrogenesis. MiR-181a was upregulated during chondrogenesis of MSC, along with an increase of the hypertrophic phenotype in resulting cartilaginous tissue. By in silico analysis combined with miR reporter assay, the WNT signaling activator and BMP signaling repressor RSPO2 was suggested as a target of miR-181a. Further validation experiments confirmed that miR-181a targets RSPO2 mRNA in MSC. It was found that in human MSC miR-181a activated BMP signaling manifested by the accumulation of SOX9 protein and increased phosphorylation of SMAD1/5/9. These effects, together with the concomitant reduction of canonical WNT signaling induced by miR-181a mimic, were in accordance with the effects expected by the loss of RSPO2, thus indicating the causative link between miR-181a and RSPO2. Moreover, we observed that a tight correlation between miR-181a and miR-218 expression levels in healthy human cartilage tissue was disrupted in osteoarthritis (OA) highlighting the importance of the WNT-BMP signaling crosstalk for preventing OA.https://www.frontiersin.org/articles/10.3389/fcell.2021.747057/fullmiR-181amesenchymal stromal cells (MSC)chondrogenesisosteoarthritis (OA)RSPO2WNT signaling |
| spellingShingle | Svitlana Melnik Nina Hofmann Jessica Gabler Nicole Hecht Wiltrud Richter MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells Frontiers in Cell and Developmental Biology miR-181a mesenchymal stromal cells (MSC) chondrogenesis osteoarthritis (OA) RSPO2 WNT signaling |
| title | MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells |
| title_full | MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells |
| title_fullStr | MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells |
| title_full_unstemmed | MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells |
| title_short | MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells |
| title_sort | mir 181a targets rspo2 and regulates bone morphogenetic protein wnt signaling crosstalk during chondrogenic differentiation of mesenchymal stromal cells |
| topic | miR-181a mesenchymal stromal cells (MSC) chondrogenesis osteoarthritis (OA) RSPO2 WNT signaling |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.747057/full |
| work_keys_str_mv | AT svitlanamelnik mir181atargetsrspo2andregulatesbonemorphogeneticproteinwntsignalingcrosstalkduringchondrogenicdifferentiationofmesenchymalstromalcells AT ninahofmann mir181atargetsrspo2andregulatesbonemorphogeneticproteinwntsignalingcrosstalkduringchondrogenicdifferentiationofmesenchymalstromalcells AT jessicagabler mir181atargetsrspo2andregulatesbonemorphogeneticproteinwntsignalingcrosstalkduringchondrogenicdifferentiationofmesenchymalstromalcells AT nicolehecht mir181atargetsrspo2andregulatesbonemorphogeneticproteinwntsignalingcrosstalkduringchondrogenicdifferentiationofmesenchymalstromalcells AT wiltrudrichter mir181atargetsrspo2andregulatesbonemorphogeneticproteinwntsignalingcrosstalkduringchondrogenicdifferentiationofmesenchymalstromalcells |