Periodic Reporting for period 3 - BONEPHAGY (Defining the role of the FGF – autophagy axis in bone physiology)
Période du rapport: 2020-01-01 au 2021-06-30
a) Define the molecular mechanisms by which FGF signaling control autophagy FGF-autophagy axis.
b) To determine the physiological relevance of autophagy regulation by FGF signaling.
c) Develop new therapeutic approaches for disorders due to mutations in the FGF signaling pathway.
In addition, we are performing a systematic identification of the autophagy substrates in chondrocytes and osteoblasts before and after stimulation with FGF. We have already demonstrated that a fractions of newly synthesized procollagen molecules inappropriately folded is cleared from the endoplasmic reticulum by a selective form of autophagy, known as ER-phagy. This work was recently published in EMBO Journal (Forrester et al. EMBO 2018).
Furthermore, we are investigating whether the enhancement of autophagy and lysosomal catabolism is beneficial for the treatment of genetic skeletal disorders, such as achondroplasia and lysosomal storage disorders. We have recently demonstrated that the pharmacological enhancement of autophagy ameliorates the skeletal manifestation in 2 different mouse models of lysosomal storage disorders. This work was recently published in Journal of Clinical Investigation (Bartolomeo et al. 2017).
We have identified the molecular mechanisms mediating procollagen clearance from the ER via autophagy. In the next years, we plan to identify new autophagy substrates in chondrocytes and osteoblasts through mass-spectrometry analysis on purified lysosomes. We have provided proof of principle that modulation of autophagy might be beneficial for the treatment of skeletal abnormalities in lysosomal storage disorders. In the next years we plan to investigate whether manipulation of the signaling pathway we have identified in chondrocytes might be beneficial for the treatment of FGF-related skeletal disorders.