Systemic RANK-Fc protein therapy is efficacious against primary osteosarcoma growth in a murine model via activity against osteoclasts.
OBJECTIVE
Osteosarcoma (OS) is the most common primary malignant bone tumour, and mainly affects adolescents and young adults. Although there has been substantial improvement in management of OS with surgery and chemotherapy, further survival increase has not been achieved over the past two decades.


METHODS
We focused on the receptor activator of nuclear factor kappaB ligand (RANKL)-osteoclast (OCL) system as a biological target for OS. RANKL is a critical factor for OCL formation and bone resorption activity. The primary lesion in bone and ensuing metastasis in OS both require the induction of OCLs. RANK-Fc is a potent RANKL antagonist and inhibitor of OCL formation and activity.


RESULTS
In an orthotopic model in Balb/c nu/nu mice, a twice weekly dosing regimen of 350 microg of RANK-Fc per mouse subcutaneously (n= 5) reduced lung metastasis (P > 0.05), preserved bone structure and reduced tartrate-resistant acid phosphatase (TRAP)(+) OCLs (P < 0.005) in OS-bearing bone. In vitro, RANK-Fc suppressed OCL formation (P < 0.005), bone resorption activity (P < 0.005) and RANKL-induced anti-apoptosis (P < 0.5) of OCLs.
Akiyama
Toru
T
Department of Orthopaedics and Surgery, University of Melbourne, Australia.
Dass
Crispin R
CR
Shinoda
Yusuke
Y
Kawano
Hirotaka
H
Tanaka
Sakae
S
Choong
Peter F M
PF
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000209:etiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D000071681:Tartrate-Resistant Acid Phosphatase
D007527:Isoenzymes; D053245:RANK Ligand; C517736:Rank-Fc; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase