title: Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome.
abstract: Multiple synostoses syndrome 2 (SYNS2) is a rare genetic disease characterized by multiple fusions of the joints of the extremities, like phalangeal joints, carpal and tarsal joints or the knee and elbows. SYNS2 is caused by point mutations in the Growth and Differentiation Factor 5 (GDF5), which plays an essential role during skeletal development and regeneration. We selected one of the SYNS2-causing GDF5 mutations, p.N445T, which is known to destabilize the interaction with the Bone Morphogenetic Protein (BMP) antagonist NOGGIN (NOG), in order to generate the superagonistic GDF5 variant GDF5(N445T). In this study, we tested its capacity to support regeneration in a rat critical-sized defect model in vivo. MicroCT and histological analyses indicate that GDF5(N445T)-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5(wt))-treated defects. Microarray-based gene expression and quantitative PCR analyses from callus tissue point to a specific acceleration of the early phases of bone healing, comprising the inflammation and chondrogenesis phase. These results support the concept that disease-deduced growth factor variants are promising lead structures for novel therapeutics with improved clinical activities.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Degenkolbe
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Research Group Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Claus-Eric
authors.initials: CE
authors.lastname: Ott
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: König
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schmidt-Bleek
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Ellinghaus
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Lienau
authors.affiliation: Biopharm GmbH, 69115 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Plöger
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Research Group Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Georg N
authors.initials: GN
authors.lastname: Duda
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Willie
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Research Group Development and Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. Electronic address: petra.seemann@charite.de.
authors.forename: Petra
authors.initials: P
authors.lastname: Seemann
mesh_terms: D000818:Animals; D005260:Female; D055428:Growth Differentiation Factor 5 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017354:Point Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013580:Synostosis / Q000235:genetics / Q000503:physiopathology*; D014158:Transcription, Genetic; D014945:Wound Healing
chemical_list: C000594129:GDF5 protein, rat; D055428:Growth Differentiation Factor 5
keywords: Bone Morphogenetic Proteins; Bone healing; Endochondral bone formation; Growth and Differentiation Factor 5; Inflammation; NOGGIN