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  Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome

Degenkolbe, E., Schwarz, C., Ott, C. E., Konig, J., Schmidt-Bleek, K., Ellinghaus, A., et al. (2015). Improved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome. Bone, 73, 111-119. doi:10.1016/j.bone.2014.12.017.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-783D-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-783E-5
Genre: Journal Article

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 Creators:
Degenkolbe, E., Author
Schwarz, C., Author
Ott, C. E.1, Author
Konig, J., Author
Schmidt-Bleek, K., Author
Ellinghaus, A., Author
Schmidt, T., Author
Lienau, J., Author
Ploger, F., Author
Mundlos, S.2, Author              
Duda, G. N., Author
Willie, B. M., Author
Seemann, P.2, Author              
Affiliations:
1Max Planck Society, ou_persistent13              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Growth and Differentiation Factor 5; NOGGIN; Bone Morphogenetic Proteins; Bone healing; Inflammation; Endochondral bone formation
 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.

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Language(s): eng - English
 Dates: 2014-12-242015-04
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.bone.2014.12.017
ISSN: 1873-2763 (Electronic)1873-2763 (Print)
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Title: Bone
  Other : Bone
Source Genre: Journal
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Publ. Info: New York : Elsevier
Pages: - Volume / Issue: 73 Sequence Number: - Start / End Page: 111 - 119 Identifier: ISSN: 8756-3282
CoNE: https://pure.mpg.de/cone/journals/resource/954927629281