title: NELL1 promotes bone regeneration in polyethylene particle-induced osteolysis.
abstract: We investigated the therapeutic effects of a craniosynostosis-associated molecule, NEL-like molecule-1 (NELL1; NEL [a protein strongly expressed in neural tissue encoding the epidermal growth factor-like domain]), on osteolysis induced by polyethylene (PE)-particle debris. We used a murine calvarial osteolysis model with in vivo adenovirus (Ad)-mediated gene transfer. In total, 76 female Balb/c mice were randomly assigned to four groups for treatment 1 day postoperation: SHAM (injected with 0.1 mL saline without implantation of particles); PE control (injected with 0.1 mL saline after implantation of particles); PE+(Ad-GFP-NELL1) (injected with 0.1 mL Ad-GFP-NELL1 in saline after implantation of particles); and PE+(Ad-GFP) group (injected with 0.1 mL Ad-GFP in saline after implantation of particles). Green fluorescent protein (GFP) and NELL1 delivery in vivo after the injection were validated by optical imaging at 10 day postop, and then, all mice were sacrificed for analysis by three-dimensional (3D) microcomputed tomography (micro-CT), real-time polymerase chain reaction (PCR), histology, and biomechanical testing. Exogenous NELL1 and GFP were expressed in the osteolysis area for at least 9 days after the Ad-GFP-NELL1 injection. Serial 3D micro-CT images and testing of bone volume, bone mineral density, trabecular thickness, bone surface density, and connectivity density revealed that the new bone promoted with the Ad-GFP-NELL1 injection could almost compensate the PE-induced osteolysis and regenerate significantly better than with the Ad-GFP treatment. The expression of osteopontin (OPN) was significantly higher with Ad-GFP-NELL1 transduction among all the samples. Real-time PCR examination confirmed the augmented expression of OPN, Runx-2, and receptor activator of nuclear factor-kappa B ligand (RANKL). The elastic modulus was significantly greater with Ad-GFP-NELL1 than with the PE and/or Ad-GFP group (p<0.01). We found no transgene-associated toxic effects. Ad-GFP-NELL1 gene transfer effectively reversed the calvarial osteolysis and could be considered a new treatment for osteolysis through promoting bone regeneration.
authors.affiliation: Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Guo
authors.forename: Jiang
authors.initials: J
authors.lastname: Peng
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Aiyuan
authors.initials: A
authors.lastname: Wang
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: Yuan
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Xue
authors.forename: Quanyi
authors.initials: Q
authors.lastname: Guo
authors.forename: Wenjing
authors.initials: W
authors.lastname: Xu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Shibi
authors.initials: S
authors.lastname: Lu
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D001861:Bone Regeneration; D002135:Calcium-Binding Proteins; D055119:Elastic Modulus; D005260:Female; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D010014:Osteolysis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D011095:Polyethylenes / Q000009:adverse effects*; D060888:Real-Time Polymerase Chain Reaction; D012886:Skull / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D014161:Transduction, Genetic; D055114:X-Ray Microtomography
chemical_list: D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins; D011095:Polyethylenes; D049452:Green Fluorescent Proteins