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BMPR2-pSMAD1/5 signaling pathway regulates RUNX2 expression and impacts the progression of dedifferentiated chondrosarcoma.

ABSTRACT: Bone morphogenetic protein receptors (BMPRs) are multifunctional proteins; they have indispensible roles in the process of BMP signaling. However, their function in dedifferentiated chondrosarcoma is uncertain. It has been reported that BMPR2 is associated with chondrosarcoma. Moreover, the detection of BMPR2 is more frequent in dedifferentiated chondrosarcomas (DDCS) than in conventional chondrosarcomas (CCS). BMPR2, phospho-SMAD1/5 (pSMAD1/5), and runt-related transcription factor 2 (RUNX2) expressions were found to be associated with the pathological grades of chondrosarcoma and could be a promising target of treatment outcome. Moreover, BMPR2 was found to induce the RUNX2 expression via pSmad1/5. Knockdown of BMPR2 and pSmad1/5 results in the downregulation of RUNX2 expression in DDCS cells, while the upregulation of BMPR2 and Smad1/5 in CCS cells leads to increased RUNX2 expression. The luciferase reporter gene assay suggested that BMPR2 can induce the RUNX2 expression at the transcriptional level. By chromatin immunoprecipitation (ChIP) and electrophoresis mobility shift assay (EMSA), it was found that pSmad1/5 combined directly to RUNX2. The in vivo tumorigenicity assay in mice showed that the inhibition of BMPR2 or Smad1/5 in DDCS cell line reduced tumor growth, while the upregulation of BMPR2 or Smad1/5 in CCS cell line increased tumor growth. Furthermore, a BMPR signaling inhibitor, LDN-193189, was introduced to investigate its role as a potential drug to treat DDCS. Taken together, the present-study results suggest that BMPR2-pSmad1/5 signaling pathway has an important role in regulating not only the RUNX2 expression but also the tumorigenesis of DDCS.

SUBMITTER: Yang K

PROVIDER: S-EPMC4937734 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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BMPR2-pSMAD1/5 signaling pathway regulates RUNX2 expression and impacts the progression of dedifferentiated chondrosarcoma.

Yang Kang K Tang Xiao-Dong XD Guo Wei W Xu Xiao-Long XL Ren Ting-Ting TT Ren Cong-Min CM Wang Shi-Dong SD Bao Xing X Zhang Fan F Sun Kun-Kun KK

American journal of cancer research 20160601 6

Bone morphogenetic protein receptors (BMPRs) are multifunctional proteins; they have indispensible roles in the process of BMP signaling. However, their function in dedifferentiated chondrosarcoma is uncertain. It has been reported that BMPR2 is associated with chondrosarcoma. Moreover, the detection of BMPR2 is more frequent in dedifferentiated chondrosarcomas (DDCS) than in conventional chondrosarcomas (CCS). BMPR2, phospho-SMAD1/5 (pSMAD1/5), and runt-related transcription factor 2 (RUNX2) ex ...[more]

PMID: 27429845

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Project description:Notch signaling is involved in the early onset of osteoarthritis. The aim of this study was to investigate the role of Notch signaling changes during proliferation and differentiation of chondrocyte, and to testify the mechanism of MMP-13 regulation by Notch and Runx2 expression changes during osteoarthritis. In this study, Chondrocytes were isolated from rat knee cartilages. Notch signaling was activated/inhibited by Jagged-1/DAPT. Proliferative capacity of Chondrocytes was analyzed by CCK-8 staining and EdU labeling. ColX, Runx2 and MMP-13 expressions were analyzed as cell differentiation makers. Then, Runx2 gene expression was interfered using lentivirus transfection (RNAi) and was over-expressed by plasmids transfected siRNA in chondrocytes, and MMP-13 expression was analyzed after Jagged-1/DAPT treatment. In vivo, an intra-articular injection of shRunx2 lentivirus followed with Jagged1/DAPT treatments was performed in rats. MMP-13 expression in articular cartilage was detected by immunohistochemistry. Finally, MMP-13 expression changes were analyzed in chondrocytes under IL-1β stimulation. Our findings showed that, CCK-8 staining and EdU labeling revealed suppression of cell proliferation by Notch signaling activation after Jagged-1 treatment in chondrocytes. Promoted differentiation was also observed, characterized by increased expressions of Col X, MMP-13 and Runx2. Meanwhile, Sox9, aggrecan and Col II expressions were down-regulated. The opposite results were observed in Notch signaling inhibited cells by DAPT treatment. In addition, Runx2 RNAi significantly attenuated the 'regulatory sensitivity' of Notch signaling on MMP-13 expression both in vitro and in vivo. However, we found there wasn't significant changes of this 'regulatory sensitivity' of Notch signaling after Runx2 over-expression. Under IL-1β circumstance, MMP-13 expression could be reduced by both DAPT treatment and Runx2 RNAi, while Runx2 interference also attenuated the 'regulatory sensitivity' of Notch in MMP-13 under IL-1β stimulation. In conclusion, Notch signaling is an important regulator on rat chondrocyte proliferation and differentiation, and this regulatory effect was partially mediated by proper Runx2 expression under both normal and IL-1β circumstances. In the meanwhile, DAPT treatment could effectively suppress expression of MMP-13 stimulated by IL-1 β.

Dataset Information

BMPR2-pSMAD1/5 signaling pathway regulates RUNX2 expression and impacts the progression of dedifferentiated chondrosarcoma.

Publications

BMPR2-pSMAD1/5 signaling pathway regulates RUNX2 expression and impacts the progression of dedifferentiated chondrosarcoma.

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