title: Variants of Osteoprotegerin Lacking TRAIL Binding for Therapeutic Bone Remodeling in Osteolytic Malignancies.
abstract: Osteolytic bone damage is a major cause of morbidity in several metastatic pathologies. Current therapies using bisphosphonates provide modest improvement, but cytotoxic side effects still occur prompting the need to develop more effective therapies to target aggressive osteoclastogenesis. Increased levels of receptor activator of NF-κB ligand (TNFSF11/RANKL), leading to RANKL-RANK signaling, remain the key axis for osteoclast activation and bone resorption. Osteoprotegerin (TNFRSF11B/OPG), a decoy receptor for RANKL, is significantly decreased in patients who present with bone lesions. Despite its potential in inhibiting osteoclast activation, OPG also binds to TNF-related apoptosis-inducing ligand (TNFSF10/TRAIL), making tumor cells resistant to apoptosis. Toward uncoupling the events of TRAIL binding of OPG and to improve its utility for bone remodeling without inducing tumor resistance to apoptosis, OPG mutants were developed by structural homology modeling based on interactive domain identification and by superimposing models of OPG, TRAIL, and its receptor DR5 (TNFRSF10B) to identify regions of OPG for rational design. The OPG mutants were purified and extensively characterized for their ability to decrease osteoclast damage without affecting tumor apoptosis pathway both in vitro and in vivo, confirming their potential in bone remodeling following cancer-induced osteolytic damage.
  
  
  CONCLUSIONS
  OPG variants were developed that lack TRAIL binding, yet retain RANKL binding and suggest new possibilities for therapeutic targeting in osteolytic malignancies.
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: Jerome T
authors: JT
authors: Higgs
authors: Department of Biochemistry, The University of Alabama at Birmingham, Birmingham, Alabama. Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: John S
authors: JS
authors: Jarboe
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: Joo Hyoung
authors: JH
authors: Lee
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: Diptiman
authors: D
authors: Chanda
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: Carnellia M
authors: CM
authors: Lee
authors: Department of Vision Sciences, The University of Alabama at Birmingham, Birmingham, Alabama.
authors: Champion
authors: C
authors: Deivanayagam
authors: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama. pons@uab.edu.
authors: Selvarangan
authors: S
authors: Ponnazhagan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D016723:Bone Remodeling; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis; D053244:Osteoprotegerin / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053244:Osteoprotegerin; D053221:TNF-Related Apoptosis-Inducing Ligand; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human
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