title: Superior angiogenic potential of GDF-5 and GDF-5(V453/V456) compared with BMP-2 in a rabbit long-bone defect model.
abstract: BACKGROUND
  The clinical application of bone morphogenetic proteins such as BMP-2 and GDF-5 (growth and differentiation factor-5) may improve the outcome of bone defect repair. In addition to the osteoinductivity of BMPs, their angiogenic potential is important as an adequate blood supply is a prerequisite for bone-healing. We used a rabbit long-bone defect model to investigate whether angiogenicity and osteogenicity were correlated features of a BMP molecule by comparing the induction of blood vessel and bone formation by BMP-2, GDF-5, and a previously created swap mutant GDF-5V453/V456 (BB-1) with elevated BMP receptor-IA binding.
  
  
  METHODS
  Microcomputed tomography and immunohistochemistry were used to assess early bone formation and neovascularization in 15-mm (critical-sized) rabbit radius defects treated with a growth factor-loaded collagen carrier.
  
  
  RESULTS
  Blood vessel volume and surface area on days 7 and 14 after surgery were significantly greater in defects treated with GDF-5 and with BB-1 compared with controls (p < 0.05); BMP-2 enhanced vascularization on day 14 (p < 0.05). Cumulative data including both time points reflected increased vessel volume, intersection surface area, and number of vessels after treatment with GDF-5 and BB-1 compared with BMP-2 (p < 0.05), corresponding to the histology results. Each of the growth factors resulted in enhanced bone formation compared with controls on day 14 (p < 0.01), with BB-1 resulting in significantly more bone compared with GDF-5 as indicated by bone volume and surface area (p = 0.006).
  
  
  CONCLUSIONS
  Both GDF-5 and BB-1 had high angiogenicity, and BB-1 outperformed GDF-5 with respect to osteogenicity. Strong induction of bone formation by BMP-2 and BB-1 was thus associated with BMP receptor-IA-dependent signaling, whereas the vascularization outcome was not.
  
  
  CONCLUSIONS
  Although both BMP-2 and the GDF-5 variant BB-1 are good inducers of bone formation, BB-1 is especially promising for long-bone healing if high angiogenicity is desired along with high osteogenicity to promote recreation of optimal bone architecture.
authors.affiliation: Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. E-mail address for W. Richter: wiltrud.richter@med.uni-heidelberg.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kleinschmidt
authors.affiliation: Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. E-mail address for W. Richter: wiltrud.richter@med.uni-heidelberg.de.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Wagner-Ecker
authors.affiliation: Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. E-mail address for W. Richter: wiltrud.richter@med.uni-heidelberg.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bartek
authors.affiliation: Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. E-mail address for W. Richter: wiltrud.richter@med.uni-heidelberg.de.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Holschbach
authors.affiliation: Research Centre for Experimental Orthopaedics, Heidelberg University Hospital, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. E-mail address for W. Richter: wiltrud.richter@med.uni-heidelberg.de.
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017102:Fracture Healing / Q000187:drug effects*; D055428:Growth Differentiation Factor 5 / Q000235:genetics / Q000494:pharmacology*; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects; D011817:Rabbits; D011885:Radius Fractures / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D055396:Bone Morphogenetic Protein 2; D055428:Growth Differentiation Factor 5; D052005:Bone Morphogenetic Protein Receptors, Type I