title: Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model.
abstract: OBJECTIVE
  To evaluate healing of surgically created large osteochondral defects in a weight-bearing femoral condyle in response to delayed percutaneous direct injection of adenoviral (Ad) vectors containing coding regions for either human bone morphogenetic proteins 2 (BMP-2) or -6.
  
  
  METHODS
  Four 13mm diameter and 7mm depth circular osteochondral defects were drilled, 1/femoral condyle (n=20 defects in five ponies). At 2 weeks, Ad-BMP-2, Ad-BMP-6, Ad-green fluorescent protein (GFP), or saline was percutaneously injected into the central drill hole of the defect. Quantitative magnetic resonance imaging (qMRI) and computed tomography (CT) were serially performed at 12, 24, and 52 weeks. At 12 (one pony) or 52 weeks, histomorphometry and microtomographic analyses were performed to assess subchondral bone and cartilage repair tissue quality.
  
  
  RESULTS
  Direct delivery of Ad-BMP-6 demonstrated delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and histologic evidence of greater Glycosaminoglycan (GAG) content in repair tissue at 12 weeks, while Ad-BMP-2 had greater non-mineral cartilage at the surface at 52 weeks (p<0.04). Ad-BMP-2 demonstrated greater CT subchondral bone mineral density (BMD) by 12 weeks and both Ad-BMP-2 and -6 had greater subchondral BMD at 52 weeks (p<0.05). Despite earlier (Ad-BMP-6) and more persistent (Ad-BMP-2) chondral tissue and greater subchondral bone density (Ad-BMP-2 and -6), the tissue within the large weight-bearing defects at 52 weeks was suboptimal in all groups due to poor quality repair cartilage, central fibrocartilage retention, and central bone cavitation. Delivery of either BMP by this method had greater frequency of subchondral bone cystic formation (p<0.05).
  
  
  CONCLUSIONS
  Delivery of Ad-BMP-2 or Ad-BMP-6 via direct injection supported cartilage and subchondral bone regeneration but was insufficient to provide long-term quality osteochondral repair.
authors.affiliation: Comparative Orthopaedic Research Laboratory, Department of Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Menendez
authors.forename: D J
authors.initials: DJ
authors.lastname: Clark
authors.forename: M
authors.initials: M
authors.lastname: Carlton
authors.forename: D C
authors.initials: DC
authors.lastname: Flanigan
authors.forename: G
authors.initials: G
authors.lastname: Jia
authors.forename: S
authors.initials: S
authors.lastname: Sammet
authors.forename: S E
authors.initials: SE
authors.lastname: Weisbrode
authors.forename: M V
authors.initials: MV
authors.lastname: Knopp
authors.forename: A L
authors.initials: AL
authors.lastname: Bertone
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015519:Bone Density; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology* / Q000627:therapeutic use; D055418:Bone Morphogenetic Protein 6 / Q000494:pharmacology* / Q000627:therapeutic use; D001861:Bone Regeneration / Q000187:drug effects / Q000502:physiology*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005269:Femur / Q000502:physiology; D019786:Gadolinium DTPA; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006025:Glycosaminoglycans / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006614:Hindlimb / Q000502:physiology; D006736:Horses; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D014057:Tomography, X-Ray Computed; D016474:Weight-Bearing
chemical_list: D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D006025:Glycosaminoglycans; D049452:Green Fluorescent Proteins; D019786:Gadolinium DTPA