Knockdown of Bone Morphogenetic Proteins Type 1a Receptor (BMPR1a) in Breast Cancer Cells Protects Bone from Breast Cancer-Induced Osteolysis by Suppressing RANKL Expression

Cell Physiol Biochem. 2018;45(5):1759-1771. doi: 10.1159/000487784. Epub 2018 Feb 23.


Background/aims: Bone morphogenetic proteins (BMPs) and BMP receptors widely participate in osteolytic metastasis of breast cancer, while their role in tumor-stromal interaction is largely unknown. In this study, we investigated whether BMP receptor type 1a (BMPR1a) can alter the interaction between metastatic cancer cells and osteoclast precursors.

Methods: Adenovirus-mediated RNA interference was used to interrupt target genes of human breast cancer cell lines and nude mice were injected intratibially with the cancer cells. Tumor-bearing mice were examined by bioluminescence imaging and microCT. Sections of metastatic legs were measured by a series of staining methods. Murine bone marrow mononuclear cells or RAW264.7 cells were cultured with conditioned media of breast cancer cells. RT-PCR, Western blotting and ELISA were used to test mRNA and protein expressions of target molecules.

Results: Expression of BMPR1a of MDA-MB-231-luc cells at tumor-bone interface was apparently stronger than that of cancer cells distant from the interface. Mice injected with BMPR1a-knockdown MDA-MB-231-luc cells showed reduced tumor growth and bone destruction compared with control groups. Knockdown (KD) of BMPR1a of MDA-MB-231-luc cells or MCF-7 cells decreased the level of receptor activator for NF-κB ligand (RANKL). Level of RANKL in MDA-MB-231-luc cells or MCF-7 cells was reduced by p38 inhibitor. Compared with control group, knockdown of p38 of breast cancer cells decreased cancer-induced osteoclastogenesis.

Conclusion: Knockdown of BMPR1a of breast cancer cells suppresses their production of RANKL via p38 pathway and inhibits cancer-induced osteoclastogenesis, which indicates that BMPR1a might be a possible target in breast cancer-induced osteolytic metastasis.

Keywords: Bmpr1a; Bone metastasis; Breast cancer; Osteoclastogenesis; Osteolysis; Tumor-stromal interaction.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bone Morphogenetic Protein Receptors, Type I / antagonists & inhibitors
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Protein Receptors, Type I / metabolism*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Culture Media, Conditioned / pharmacology
  • Down-Regulation / drug effects
  • Female
  • Humans
  • Imidazoles / pharmacology
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Osteogenesis / drug effects
  • Pyridines / pharmacology
  • RANK Ligand / metabolism*
  • RAW 264.7 Cells
  • RNA Interference
  • Signal Transduction / drug effects
  • Tibia / diagnostic imaging
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Culture Media, Conditioned
  • Imidazoles
  • Pyridines
  • RANK Ligand
  • p38 Mitogen-Activated Protein Kinases
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I
  • SB 203580