BACKGROUND: This study investigated the effects of the receptor activator for nuclear factor kappaB ligand (RANKL) inhibitor, osteoprotegerin (OPG), on tumor-induced allodynia, osteolysis, and bone histology in the mammary tumor (MRMT-1) rat model for bone cancer pain. METHODS: Rats (n = 8/group) were inoculated with MRMT-1 or culture medium in the proximal right tibia, injected with OPG or vehicle subcutaneously 2-3 times weekly, evaluated for mechanical allodynia with von Frey paw stimulation, and euthanized on Day 20 for necropsy. Three groups were evaluated starting on Day 5 and received the following interventions beginning on Day 1: tumor and OPG, tumor and vehicle, or culture medium and vehicle. Three additional groups received the same interventions but were evaluated starting on Day 3. A seventh group started OPG on Day 8 after tumor inoculation. RESULTS: Starting OPG on Day 1 reduced allodynia significantly compared with vehicle injections; pain relief was observed within 5-6 days after tumor inoculation and lasted throughout follow-up. Starting OPG on Day 8 did not reverse allodynia significantly compared with the tumor control group. Regardless of treatment start time, OPG treatment reduced osteoclast number and tartrate-resistant acid phosphatase levels, increased bone mineral density, preserved normal bone volume and integrity on micro-computed tomography, reduced relative tumor volume in the bone, and reduced staining for glial fibrillary acidic protein in the spinal cord. CONCLUSIONS: RANKL inhibition with OPG reduced bone resorption and bone pain in rats with malignant bone disease; further study is warranted to determine if RANKL inhibition has similar benefits in humans.
BACKGROUND: This study investigated the effects of the receptor activator for nuclear factor kappaB ligand (RANKL) inhibitor, osteoprotegerin (OPG), on tumor-induced allodynia, osteolysis, and bone histology in the mammary tumor (MRMT-1) rat model for bone cancer pain. METHODS:Rats (n = 8/group) were inoculated with MRMT-1 or culture medium in the proximal right tibia, injected with OPG or vehicle subcutaneously 2-3 times weekly, evaluated for mechanical allodynia with von Frey paw stimulation, and euthanized on Day 20 for necropsy. Three groups were evaluated starting on Day 5 and received the following interventions beginning on Day 1: tumor and OPG, tumor and vehicle, or culture medium and vehicle. Three additional groups received the same interventions but were evaluated starting on Day 3. A seventh group started OPG on Day 8 after tumor inoculation. RESULTS: Starting OPG on Day 1 reduced allodynia significantly compared with vehicle injections; pain relief was observed within 5-6 days after tumor inoculation and lasted throughout follow-up. Starting OPG on Day 8 did not reverse allodynia significantly compared with the tumor control group. Regardless of treatment start time, OPG treatment reduced osteoclast number and tartrate-resistant acid phosphatase levels, increased bone mineral density, preserved normal bone volume and integrity on micro-computed tomography, reduced relative tumor volume in the bone, and reduced staining for glial fibrillary acidic protein in the spinal cord. CONCLUSIONS:RANKL inhibition with OPG reduced bone resorption and bone pain in rats with malignant bone disease; further study is warranted to determine if RANKL inhibition has similar benefits in humans.
Authors: P Honore; N M Luger; M A Sabino; M J Schwei; S D Rogers; D B Mach; P F O'keefe; M L Ramnaraine; D R Clohisy; P W Mantyh Journal: Nat Med Date: 2000-05 Impact factor: 53.440
Authors: W S Simonet; D L Lacey; C R Dunstan; M Kelley; M S Chang; R Lüthy; H Q Nguyen; S Wooden; L Bennett; T Boone; G Shimamoto; M DeRose; R Elliott; A Colombero; H L Tan; G Trail; J Sullivan; E Davy; N Bucay; L Renshaw-Gegg; T M Hughes; D Hill; W Pattison; P Campbell; S Sander; G Van; J Tarpley; P Derby; R Lee; W J Boyle Journal: Cell Date: 1997-04-18 Impact factor: 41.582
Authors: N Udagawa; N Takahashi; H Yasuda; A Mizuno; K Itoh; Y Ueno; T Shinki; M T Gillespie; T J Martin; K Higashio; T Suda Journal: Endocrinology Date: 2000-09 Impact factor: 4.736
Authors: Molly A Sevcik; Nancy M Luger; David B Mach; Mary Ann C Sabino; Christopher M Peters; Joseph R Ghilardi; Matthew J Schwei; Heidi Röhrich; Carmen De Felipe; Michael A Kuskowski; Patrick W Mantyh Journal: Pain Date: 2004-09 Impact factor: 6.961
Authors: David L Lacey; William J Boyle; W Scott Simonet; Paul J Kostenuik; William C Dougall; John K Sullivan; Javier San Martin; Roger Dansey Journal: Nat Rev Drug Discov Date: 2012-05 Impact factor: 84.694