Title

Regulation of Osteoblast Migration by Receptor Activator of Nuclear Factor kappa B (RANK) Signaling

Date of Completion

January 2010

Keywords

Biology, Molecular|Biology, Cell

Degree

Ph.D.

Abstract

Bone remodeling is a dynamic process that requires osteoclast activation, resorption and reversal, prior to osteoblast migration into the bone resorption cavity. RANKL (Receptor Activator of NF-kappa B Ligand) and OPG (Osteoprotegrin) are expressed by osteoblasts, while RANK (Receptor Activator of NF-kappa B) is expressed as a receptor on osteoclasts and controls activation, differentiation, and migration of osteoclasts (Teitelbaum and Ross, 2003). Recent data suggest a role for RANK in migration of primary and secondary bone metastases (Mori et al., 2007b; Armstrong et al., 2008; Jones et al., 2006). We found RANK to be expressed in pre-osteoblasts as well. Soluble RANKL (sRANKL) bound to RANK and activated the phosphorylation of ERK, p38 MAPK, Akt and p65 NFkB, suggesting that RANK was functional. RANK expression was down regulated during differentiation in the immortalized human preosteoblastic cell line hFOB 1.19 by Western blot analysis. Modified Boyden chamber assays and wound repair assays showed that sRANKL generated a chemotactic response on osteoblasts only in the presence of ERK pathway inhibitor, suggesting a role for RANK in pre-osteoblast migration. ^ Data from our laboratory also suggests that the RANK protein is overexpressed in primary tumors and in osteosarcoma cell lines. RANK mutations do not appear critical for the development of osteosarcoma (Sparks et al., 2001). Therefore, the variable expression of RANK observed in osteosarcoma tumors might be due to the differentiation state of the tumor with respect to the osteoprogenitor lineage. Our hypothesis is that RANK signaling regulates osteoblast migration. The focus of this thesis is to broaden the knowledge of the regulation of the osteoblast and to show a paradigm shift for the role of RANK during bone remodeling. ^