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Recently, in the AISAC congress (an italian association for the study and information on achondroplasia), a research project by TIGEM - Telethon Institute of Genetics and Medicine was presented who's head researcher Prof. Carmine Settembre: "FGF signalling regulates bone growth through autophagy". This study was published in December 2015 in Nature.

In October 2015, a paper about autophagy related to achondroplasia was published by Chen et al. and was posted here in Beyond Achondroplasia:  FGFR3/Fibroblast Growth Factor Receptor 3 Inhibits Autophagy through Decreasing the ATG12–ATG5 Conjugate, Leading to the Delay of Cartilage Development in Achondroplasia.

Meanwhile, I contacted Prof. Settembre for some questions:

Beyond Achondroplasia:  In your paper, you say that "we show that autophagy is induced in growth plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM". Knowing that during the pre-natal time, the growth rate of the skeleton is very high, a reduction of the growth rate in the post-natal is just a natural adjustment. One of your conclusions is that autophagy produces a catabolic effect in the growth plate during the post-natal period. What is your perspective of studying autophagy in chondrocytes with the mutation of achondroplasia?

Carmine Settembre: We are studying the role of autophagy in achondroplasia, since consistently with the study of Chen et. al, we do observe reduced autophagy in FGFR3-ACH expressing cells.

BA: Recently, we published an article (that you can read here) related to Chen et al., "FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia". In this work, Chen team suggested that: "Impaired autophagy in chondrocytes will result in abnormal cartilage development. However, the role of autophagy in achondroplasia is not well understood. FGF signaling may inhibit autophagic activity in chondrocytes, which may be involved in the pathogenesis of achondroplasia". Do you see a direct link between the reduction of autophagy in chondrocytes and the reduction of the mutated FGFR3 in these chondrocytes, in a case of achondroplasia?

CS:  I have already seen and read with great interest this article. We are studying the role of autophagy in achondroplasia, since consistently with the study of Chen et. al we do observe reduced autophagy in FGFR3-ACH expressing cells. A crucial question to address is to understand the relevance of autophagy in ACH pathogenesis, since many different pathways may contribute to the ACH phenotype. We have in our lab all the tools to address this question and we are committed to do it. At this point, we don'€™t know how the mutated FGFR3 inhibits autophagy. We are exploring a different possibility, including the direct interaction with autophagy proteins, as proposed in Chen et al.  Currently, I don'€™t think we can predict that autophagy enhancement will improve bone length in ACH. This is the reason why we are doing this kind of experiments. 

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