Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue.
Giant-cell tumor of bone (GCTB) and giant-cell tumor of soft tissue (GCTST) are tumors that contain a prominent osteoclastlike giant-cell component. The precise relationship between these morphologically similar tumors is unclear, and the cellular mechanism whereby giant cells accumulate within these and other locally aggressive tumors is uncertain. In this study, we have examined the cytochemical, functional, and molecular phenotype of the mononuclear and multinucleated components of GCTB and GCTST. Giant cells in GCTB and GCTST exhibited an osteoclast phenotype expressing tartrate-resistant acid phosphatase and vitronectin receptor and being capable of lacunar resorption. The mononuclear stromal cells derived from GCTB and GCTST exhibited an osteoblast phenotype, expressing alkaline phosphatase, and the receptor activator for nuclear factor kappaB ligand (RANKL), a factor that is essential for osteoclast formation. These cells also expressed osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, and TRAIL, a receptor that binds OPG. Lacunar resorption by giant cells isolated from GCTB and GCTST was inhibited by OPG, zoledronate, and calcitonin. These findings indicate that the mononuclear and giant-cell components of GCTB and GCTST have similar phenotypic features and that the accumulation of osteoclasts in these giant-cell-rich tumors occurs by a RANKL-dependent process. RANKL expression by osteoblastlike mononuclear stromal cells in these tumors stimulates osteoclast formation and resorption; this would account for the osteolysis associated with these giant-cell-rich tumors. Inhibitors of osteoclast formation and activity are likely to be effective in controlling the osteolysis associated with GCTB and possibly other giant-cell-rich lesions.
Lau
Yu Sin
YS
Department of Pathology, University of Oxford, Nuffield Orthopaedic Centre, OX3 7LD Oxford, UK.
Sabokbar
Afsaneh
A
Gibbons
C L M H
CL
Giele
Henk
H
Athanasou
Nicholas
N
D051017:Apoptosis Regulatory Proteins; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption; D002352:Carrier Proteins / Q000378:metabolism; D018920:Coculture Techniques; D018212:Giant Cell Tumor of Bone / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005870:Giant Cell Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis; D053244:Osteoprotegerin; D010641:Phenotype; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; C505688:TNFSF11 protein, human; D014409:Tumor Necrosis Factor-alpha