BMPR2-pSMAD1/5 Signaling Pathway Regulates RUNX2 Expression and Impacts the Progression of Dedifferentiated Chondrosarcoma

Kang Yang  ¹ , Xiao-Dong Tang  ¹ , Wei Guo  ¹ , Xiao-Long Xu  ¹ , Ting-Ting Ren  ¹ , Cong-Min Ren  ¹ , Shi-Dong Wang  ¹ , Xing Bao  ¹ , Fan Zhang  ¹ , Kun-Kun Sun  ²

• ¹ Musculoskeletal Tumor Center, Beijing Key Laboratory of Musculoskeletal Tumor, Peking University People’s Hospital Beijing 100044, People’s Republic of China.
• ² Department of Pathology, Peking University People’s Hospital Beijing 100044, People’s Republic of China.

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.

Keywords: BMPR2; Dedifferentiated chondrosarcoma; RUNX2; conventional chondrosarcoma; p-Smad1/5; progression.