Original Full Length ArticleImproved bone defect healing by a superagonistic GDF5 variant derived from a patient with multiple synostoses syndrome

- A superagonistic GDF5 variant, derived from a rare genetic disease, shows improved defect healing in a rat critical-sized defect.
- The regenerative potential of GDF5N445T might result from its NOGGIN-insensitivity and thereby bypassing the negative feedback loop.
- GDF5N445T-treated rats showed earlier downregulation of inflammatory marker genes.
- GDF5N445T-treated rats showed earlier up-regulation of chondrogenic marker genes.
- Improving growth factor signaling is a promising strategy for therapeutic applications in orthopedic surgery.

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 GDF5N445T. 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 GDF5N445T-treated defects show faster and more efficient healing compared to GDF5 wild type (GDF5wt)-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.