Sox9 Is Upstream of MicroRNA-140 in Cartilage

Nakamura, Yukio; He, Xinjun; Kato, Hiroyuki; Wakitani, Shigeyuki; Kobayashi, Tatsuya; Watanabe, Sumiko; Iida, Akiko; Tahara, Hideaki; Warman, Matthew L.; Watanapokasin, Ramida; Postlethwait, John H.

doi:10.1007/s12010-011-9404-y

Cited by 81 publications

(58 citation statements)

References 29 publications

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“…Other published miR-140 targets are mRNAs SP1, PDGFRA, SMAD3, BMP2, CXCL12, and HDAC4 [31,[33][34][35][36][37]. miR-140 has also been shown to be activated by SOX9 [38,39] and thus to correlate with SOX9 expression in embryonic and in vitro chondrogenesis [40,41]. Recently, miR-140 has also been proposed to play a role in early bone development [42].…”

Section: Discussionmentioning

confidence: 99%

microRNA-140 TargetsRALAand Regulates Chondrogenic Differentiation of Human Mesenchymal Stem Cells by Translational Enhancement ofSOX9andACAN

Karlsen

Jakobsen²,

Mikkelsen³

et al. 2014

Stem Cells and Development

113

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Lesions of articular cartilage do not heal spontaneously. One treatment strategy would be to make cartilage in the laboratory by directed chondrogenic differentiation of mesenchymal stem cells (MSCs). To promote our understanding of the molecular control of chondrogenesis, we have compared the changes in microRNAs (miRNAs) during in vitro chondrogenesis of MSCs with those observed in uncultured and dedifferentiated articular chondrocytes (ACs). Several miRNAs showed a reciprocal relationship during the differentiation of MSCs and dedifferentiation of ACs. miR-140-5p and miR-140-3p changed the most during in vitro chondrogenesis, they were the miRNAs most highly expressed in tissue-engineered chondrocytes, and they were also among the miRNAs most highly expressed in uncultured ACs. There was a 57% overlap for the 100 most highly expressed miRNAs in differentiated MSCs and uncultured ACs, but for other miRNAs, the expression pattern was quite different. We transiently and stably inhibited and overexpressed miR-140-5p and miR-140-3p in differentiating MSCs and dedifferentiating ACs, respectively, to describe global effects and identify and validate new targets. Surprisingly, SOX9 and aggrecan proteins were found to be downregulated in anti-miR-140 transduced differentiating MSCs despite unchanged mRNA levels. This suggests that miR-140 stimulates in vitro chondrogenesis by the upregulation of these molecules at the protein level. RALA, a small GTPase, was identified as a miR-140 target and knockdown experiments showed that RALA regulated SOX9 at the protein level. These observations shed new light on the effect of miR-140 for chondrogenesis in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

microRNA-140 TargetsRALAand Regulates Chondrogenic Differentiation of Human Mesenchymal Stem Cells by Translational Enhancement ofSOX9andACAN

Karlsen

Jakobsen²,

Mikkelsen³

et al. 2014

Stem Cells and Development

113

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“…These observations suggest that miR-140 plays a critical role in cartilage development and homeostasis. Recent findings indicate that Sox9 promotes miR-140 expression (24,25), although detailed regulatory mechanisms are not fully understood.…”

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confidence: 99%

L-Sox5 and Sox6 Proteins Enhance Chondrogenic miR-140 MicroRNA Expression by Strengthening Dimeric Sox9 Activity

Yamashita

Miyaki

Kato

et al. 2012

Journal of Biological Chemistry

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Background: miR-140 is a critical regulator of cartilage development and homeostasis. Results: The proximal upstream region of miR-140 has in vivo chondrogenic promoter activity and an L-Sox5/Sox6/Sox9 (Sox trio) response element. Conclusion:We reveal that L-Sox5 and Sox6 control miR-140 expression together with Sox9. Significance: Uncovering molecular mechanisms of chondrogenesis has implications for cartilage repair and restoration of tissue function.

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“…low-oxygen conditions) inducible properties (HIF1, HIF2) [32] , coupled with mesenchymal cells (e.g. the CxCL12-CXCR4 axis) [49] ; sensitivity to antirheumatics; constitutive activation of NFkappaB, the Wnt/beta-catenin cell signalling pathway, the shared cytokine and chemokine signalling pathways, and the COX-2/PGE2 pathway [50] ; finally some overlapping extraterritorial osteoclast traits of primary cancer cells [51] .…”

Section: Discussionmentioning

confidence: 99%

“…In developing zebrafish (Danio rerio), sox9a mutant (sox9a-/-) and sox9b mutant (sox9b-/-) zebrafish and SOX9 small interfering RNA in human chondrocytes, T/C-28 cells, miR-140 is regulated by the cartilage master transcription regulator Sox9 [32] . The proximal upstream region of pri-miR-140 has chondrogenic promoter activity in vivo.…”

Section: Figurementioning

confidence: 99%

MiR-140 in cancer and beyond: a brief update

Zhang

2012

JST

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Cancer chemotherapy causes many side-effects, including joint pain. We speculate that a better understanding of the common biology of cancer and osteoarthritis could help us to find out ways to cure the cancer and to alleviate pain if their shared mechanisms are responsible for joint pain and/or related side-effects. In this mini-vision and reflection, we focus on the networks of miR-140 that are involved in both cancer and osteoarthritis during development and carcinogenesis. Frontiers including autophagy, potential stem-cell therapy and early nanotechnological diagnosis of those diseases will be briefly discussed.

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Sox9 Is Upstream of MicroRNA-140 in Cartilage

Cited by 81 publications

References 29 publications

microRNA-140 TargetsRALAand Regulates Chondrogenic Differentiation of Human Mesenchymal Stem Cells by Translational Enhancement ofSOX9andACAN

microRNA-140 TargetsRALAand Regulates Chondrogenic Differentiation of Human Mesenchymal Stem Cells by Translational Enhancement ofSOX9andACAN

L-Sox5 and Sox6 Proteins Enhance Chondrogenic miR-140 MicroRNA Expression by Strengthening Dimeric Sox9 Activity

MiR-140 in cancer and beyond: a brief update

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