title: Enhanced reconstruction of long bone architecture by a growth factor mutant combining positive features of GDF-5 and BMP-2.
abstract: Non healing bone defects remain a worldwide health problem and still only few osteoinductive growth factors are available for clinical use in bone regeneration. By introducing BMP-2 residues into growth and differentiation factor (GDF)-5 we recently produced a mutant GDF-5 protein BB-1 which enhanced heterotopic bone formation in mice. Designed to combine positive features of GDF-5 and BMP-2, we suspected that this new growth factor variant may improve long bone healing compared to the parent molecules and intended to unravel functional mechanisms behind its action. BB-1 acquired an increased binding affinity to the BMP-IA receptor, mediated enhanced osteogenic induction of human mesenchymal stem cells versus GDF-5 and higher VEGF secretion than BMP-2 in vitro. Rabbit radius defects treated with a BB-1-coated collagen carrier healed earlier and with increased bone volume compared to BMP-2 and GDF-5 according to in vivo micro-CT follow-up. While BMP-2 callus often remained spongy, BB-1 supported earlier corticalis and marrow cavity formation, showing no pseudojoint persistence like with GDF-5. Thus, by combining positive angiogenic and osteogenic features of GDF-5 and BMP-2, only BB-1 restored a natural bone architecture within 12 weeks, rendering this promising growth factor variant especially promising for long bone regeneration.
authors.affiliation: Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany. kerstin.kleinschmidt@merckgroup.com
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kleinschmidt
authors.forename: Frank
authors.initials: F
authors.lastname: Ploeger
authors.forename: Joachim
authors.initials: J
authors.lastname: Nickel
authors.forename: Julia
authors.initials: J
authors.lastname: Glockenmeier
authors.forename: Pierre
authors.initials: P
authors.lastname: Kunz
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Richter
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002146:Bony Callus / Q000187:drug effects / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D055428:Growth Differentiation Factor 5 / Q000494:pharmacology*; D006736:Horses; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D050505:Mutant Proteins / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D011859:Radiography; D011884:Radius / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*
chemical_list: D055396:Bone Morphogenetic Protein 2; D055428:Growth Differentiation Factor 5; D050505:Mutant Proteins; D052005:Bone Morphogenetic Protein Receptors, Type I; D000469:Alkaline Phosphatase