Inhibition of BMPR2 or Smad1/5 suppressed chondrosarcoma tumor growth, while enhancement of BMPR2 or Smad1/5 promoted DDCS tumor growth in vivo. SCID-CB17 mice and BALB/c nude mice were subcutaneously injected either NDCS-1 or HCS2/8 cells, followed by daily treatment at the onset of tumor detection. The groups included PBS (NC, subcutaneously), LDN-193189 (3 mg/kg, intraperitoneally), BMPR2 siRNA (2 μg/mouse, subcutaneously), Smad1/Smad5 siRNA (2 μg/mouse, subcutaneously), pM/BMPR2 (30 μg/mouse, subcutaneously), and pM/Smad1/pM/Smad5 (30 μg/mouse, subcutaneously). Entranster-in vivo was used as the transfection reagent. The tumor images, weight, and volume were acquired after 4 weeks’ treatment (A-E). Western blot (F, G) analysis of various proteins in the xenograft tumors. *: P < 0.05, vs NC groups. (H) Schematic mechanisms of BMPR2-pSmad1/5 signaling pathways induced effects in DDCS cells.