title: Effects of sclerostin antibody on healing of a non-critical size femoral bone defect.
abstract: Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8 mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, 450 Broadway Street, Mail Code 6342 Redwood City, Stanford, California 94063, USA.
authors.forename: Muhammad U
authors.initials: MU
authors.lastname: Jawad
authors.forename: Kate E
authors.initials: KE
authors.lastname: Fritton
authors.forename: Ting
authors.initials: T
authors.lastname: Ma
authors.forename: Pei-Gen
authors.initials: PG
authors.lastname: Ren
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.forename: Hua Z
authors.initials: HZ
authors.lastname: Ke
authors.forename: Philip
authors.initials: P
authors.lastname: Babij
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005264:Femoral Fractures / Q000188:drug therapy* / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D006023:Glycoproteins / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D015599:Trauma Severity Indices; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D008156:Luciferases