Tumor induced osteolysis, commonly seen in metastatic bone disease, is caused by increased osteoclastic bone resorption. This cascade is caused by tumor induced cytokine signaling through the RANK to RANK ligand pathway which activates the osteoclast and encourage local bone resorption (Illustration A). Medical blockade of this pathway through the use of bisphosphonates or deactivators of the RANK/RANK ligand pathway like denosumab are an active area of current research (Illustration B). Illustration C shows a video that illustrates bone remodeling and regulation involving osteoprotegrin, RANK, RANK-ligand.
In these images, RANK is a cell surface receptor which is NOT secreted. RANK ligand is the "ligand" which is secreted by osteoblasts and binds and activates RANK receptor. Osteoprotegrin is the "decoy" receptor which blocks the action of RANK ligand binding RANK.
Nannuru et al used animal model to evaluate the regulation of RANKL expression and its functional significance in tumor-induced osteolysis. They found that increased RANK ligand expression potentiates tumor-induced osteolysis and blockade of this pathway prevents bone lysis.
In a related publication, Anastasilakis et al review the inhibition of this same cell signaling cascade and its role in the clincal treatment and prevention of complications related to metastatic bone disease such as pain and pathologic fracture.
Taranta et al report on the decreased bone mineral density associated with celiac disease. They propose a "cytokine imbalance" in the RANK, RANK ligand, Osteoprotegrin (OPG) signaling pathway as the likely cause of low bone mineral density.
Nannuru KC, Futakuchi M, Sadanandam A, Wilson TJ, Varney ML, Myers KJ, Li X, Marcusson EG, Singh RK. Enhanced expression and shedding of receptor activator of NF-kappaB ligand during tumor-bone interaction potentiates mammary tumor-induced osteolysis. Clin Exp Metastasis. 2009;26(7):797-808.
PMID:19590968 (Link to Abstract)
Anastasilakis AD, Toulis KA, Polyzos SA, Terpos E. RANKL inhibition for the management of patients with benign metabolic bone disorders. Expert Opin Investig Drugs. 2009 Aug;18(8):1085-102. Review.
PMID:19558335 (Link to Abstract)
Taranta A, Fortunati D, Longo M, Rucci N, Iacomino E, Aliberti F, Facciuto E, Migliaccio S, Bardella MT, Dubini A, Borghi MO, Saraifoger S, Teti A, Bianchi ML. Imbalance of osteoclastogenesis-regulating factors in patients with celiac disease. J Bone Miner Res. 2004 Jul;19(7):1112-21.
PMID:15176994 (Link to Abstract)