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

Abstract

Bone remodeling requires osteoclast activation, resorption, and reversal, prior to osteoblast migration into the bone pit. The Receptor Activator of NF-κB (RANK) signaling pathway plays an important role in bone remodeling. Two components of the RANK signaling pathway, RANK Ligand (RANKL) and the decoy receptor Osteoprotegerin (OPG), are expressed predominantly on the surface of osteoblasts, while RANK is principally expressed on the surface of osteoclasts. However, RANK has also been reported to be expressed on the surface of osteoblasts and osteosarcoma tumor cells. Treatment with soluble RANKL (sRANKL) of both normal osteoblasts and osteosarcoma tumor cells activated phosphorylation of ERK, p38(MAPK) , Akt, and p65(NF-κB). However, modified Boyden chamber assays and wound repair assays showed differential response to sRANKL-induced chemotactic migration in normal osteoblasts and osteosarcoma tumor cells. In contrast to previously published results, both normal osteoblasts and osteosarcoma tumor cells responded to sRANKL-induced chemotactic migration but the normal osteoblasts did so only in the presence of an ERK pathway inhibitor. For both normal and tumor cells, the chemotactic response could be blocked by inhibiting the PI3K/Akt or p65(NF-κB) pathway. Response to sRANKL in normal and tumor cells suggests a role for RANK/ERK-mediated signaling in normal osteoblasts chemotactic migration during bone remodeling that is altered or lost during osteosarcoma tumorigenesis.

RANKL signaling in bone marrow mesenchymal stem cells negatively regulates osteoblastic bone formation

“…RANK is over-expressed on osteosarcoma, 15 , 16 a mesenchymal tumor with the osteoblastic origin and regulates osteoblast migration, 16 essential to bone modeling and remodeling. The current studies imply that RANKL signaling could play a key role in osteoblastic differentiation and bone formation, which has long been underestimated.…”

RANK–RANKL signalling in cancer

“…These authors demonstrated that RANKL produced by osteoblasts and bone marrow stromal cells attracts RANK-expressing cancer cells and induces their migration. This mechanism seems to be relatively universal and was observed in prostate cancer [ 95 , 126 , 127 ], breast cancer [ 95 ], colon cancer [ 58 ], melanoma [ 95 ], oral squamous carcinomas [ 128 ], lung cancer [ 129 ], hepatocarcinoma [ 130 ], endometrial cancer [ 131 ], osteosarcoma [ 132 , 133 ] and renal cancer [ 134 ]. RANKL-induced migration is associated with specific signalling cascades, especially the activation of MAP Kinase pathways.…”

Mesenchymal Stem Cell Migration during Bone Formation and Bone Diseases Therapy

“…The receptor activator of the nuclear factor kappa B ligand (RANKL) is another factor mediating osteoblast migration. It induces chemotactic migration of the human osteoblast cell line hFOB 1.19 and the primary human osteoblast through activating phosphorylation of extracellular signal-regulated kinase (ERK), p38 (MAPK), Akt, and p65 (NF-κB) [33]. Furthermore, BMP-2 could stimulate in vitro migration of the human primary osteoblasts isolated from trabecular bone in a dose-dependent manner, suggesting BMP-2 might be involved in the chemotactic recruitment of osteoblasts during bone formation in addition to its function as a differentiation enhancer [34] (Table 1).…”