Enhanced expression and shedding of receptor activator of NF-kappaB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis.
The bone microenvironment plays a critical role in tumor-induced osteolysis and osteolytic metastasis through tumor-bone (TB)-interaction. Receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) is one of the critical signaling molecules involved in osteolysis and bone metastasis. However, the regulation and functional significance of RANKL at the TB-interface in tumor-induced osteolysis remains unclear. In this report, we examined the role of tumor-stromal interaction in the regulation of RANKL expression and its functional significance in tumor-induced osteolysis. Using a novel mammary tumor model, we identified that RANKL expression was upregulated at the TB-interface as compared to the tumor alone area. We demonstrate increased generation of sRANKL at the TB-interface, which is associated with tumor-induced osteolysis. The ratio of RANKL to osteoprotegrin (OPG), a decoy receptor for RANKL, at the TB-interface was also increased. Targeting RANKL expression with antisense oligonucleotides (RANKL-ASO), significantly abrogated tumor-induced osteolysis, decreased RANKL expression and the RANKL:OPG ratio at the TB-interface. Together, these results demonstrate that upregulation of RANKL expression and sRANKL generation at the TB-interface potentiates tumor-induced osteolysis.
Nannuru
Kalyan C
KC
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-5845, USA.
Futakuchi
Mitsuru
M
Sadanandam
Anguraj
A
Wilson
Thomas J
TJ
Varney
Michelle L
ML
Myers
Kathleen J
KJ
Li
Xiaodong
X
Marcusson
Eric G
EG
Singh
Rakesh K
RK
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008024:Ligands; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010014:Osteolysis; D053245:RANK Ligand / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D008024:Ligands; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse