title: Targeting receptor-activator of nuclear kappaB ligand in aneurysmal bone cysts: verification of target and therapeutic response.
abstract: Aneurysmal bone cyst (ABC) is a benign tumor of bone presenting as a cystic, expansile lesion in both the axial and appendicular skeleton. Axial lesions demand special consideration, because treatment-related morbidity can be devastating. In similar lesions, such as giant cell tumor of bone (GCTB), the receptor-activator of nuclear kappaB ligand (RANKL)-receptor-activator of nuclear kappaB (RANK) signaling axis is essential to tumor progression. Although ABC and GCTB are distinct entities, they both contain abundant multinucleated giant cells and are osteolytic characteristically. We hypothesize that ABCs express both RANKL and RANK similarly in a cell-type specific manner, and that targeted RANKL therapy will mitigate ABC tumor progression. Cellular expression of RANKL and RANK was determined in freshly harvested ABC samples using laser confocal microscopy. A consistent cell-type-specific pattern was observed: fibroblastlike stromal cells expressed RANKL strongly whereas monocyte/macrophage precursor and multinucleated giant cells expressed RANK. Relative RANKL expression was determined by quantitative real-time polymerase chain reaction in ABC and GCTB tissue samples; no difference in relative expression was observed (P > 0.05). In addition, we review the case of a 5-year-old boy with a large, aggressive sacral ABC. After 3 months of targeted RANKL inhibition with denosumab, magnetic resonance imaging demonstrated tumor shrinkage, bone reconstitution, and healing of a pathologic fracture. Ambulation, and bowel and bladder function were restored at 6 months. Denosumab treatment was well tolerated. Post hoc analysis demonstrated strong RANKL expression in the pretreatment tumor sample. These findings demonstrate that RANKL-RANK signal activation is essential to ABC tumor progression. RANKL-targeted therapy may be an effective alternative to surgery in select ABC presentations.
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich; Department of Orthopaedic Surgery, Grand Rapids Medical Education Partners, Grand Rapids, Mich. Electronic address: Dominic.pelle@vai.org.
authors.forename: Dominic W
authors.initials: DW
authors.lastname: Pelle
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Ringler
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich.
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Peacock
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kampfschulte
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich; Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Mich.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Scholten
authors.affiliation: Department of Pathology, Spectrum Health Medical Group, Grand Rapids, Mich.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Department of Pediatric Hematology-Oncology, Helen DeVos Children's Hospital, Grand Rapids, Mich.
authors.forename: Deanna S
authors.initials: DS
authors.lastname: Mitchell
authors.affiliation: Laboratory of Musculoskeletal Oncology, Center for Skeletal Disease and Tumor Metastasis, Van Andel Institute, Grand Rapids, Mich; Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Mich; Department of Surgery, Spectrum Health Medical Group/ Helen DeVos Children's Hospital, Grand Rapids, Mich.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Steensma
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D017824:Bone Cysts, Aneurysmal / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism; D002675:Child, Preschool; D000069448:Denosumab; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D053245:RANK Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D050794:STAT1 Transcription Factor; D000069448:Denosumab