Generation of Soluble Receptor Activator of NF-kappa B Ligand is Critical for Osteolytic Bone Metastasis
Abstract
Metastasis is an ominous sign in the progression breast cancer and bone is the most common site of metastasis in advanced disease. The bone microenvironment plays a critical role in tumor-induced osteolysis and osteolytic metastasis through tumor-bone (TB)-interaction. Receptor activator of nuclear factor-kB (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. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. Targeting RANKL expression with antisense oligonucleotides (RANKL-ASO) decreased RANKL expression and reduced osteoclast activation at TB interface leading to a significant inhibition in tumor-induced osteolysis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2009
- Accession Number
- ADA515796
Entities
People
- Kalyan C. Nannuru
Organizations
- University of Nebraska Medical Center