Beyond Achondroplasia

Growing together with Clara

The new link – autophagy in chondrocytes and achondroplasia


Why does, exactly, the mutant FGFR3 reduce so exaggeratedly chondrocyte proliferation in the growth plate?

Well, there exists genetic information about achondroplasia since 1994. Francomano and Velinov found the location of the gene on the distal short arm of chromosome 4. In the same year and shortly thereafter, Shiang and Rousseau separately, found that mutations of the gene encoding fibroblast growth factor receptor 3 (FGFR3) caused achondroplasia. And in 1996 experiments by Colvin, Deng and Naski, have found the process by which the gene mutations act on the body.

But even with all this and 21 years after the discovery of the “guilty” actor in this process, the mutation in the FGFR3 in the chondrocytes, the detailed molecular mechanism of achondroplasia remains largely unknown.

For starters, it is important to talk about the cell. The cell is an absolutely amazing piece of life and is the basic structural unit for all organisms. Imagine that a human body is a house and that each brick represents a cell.

Each cell is like a factory, with different machines. The cell has macromolecules and organeles (that are like small organs). In the following image you can see a 3D scheme of an animal cell (eukariotic cell) with the indication of several organelles. The most relevant now for this theme is the lysosome.

animal-cell (1)

Imagem taken from Glogster

Among all organelles inside the cell, the lysosome is a specialized vesicle that holds a variety of enzymes (that can act over other molecules and cellular structures and “dissolve” them). Lysosomes act in several processes:

  1. Phagocytosis – where they digest foreign material and engulf viruses and bacteria presenting in phagosomes;
  2. Autolysis – lysosomes destroy targeted organelles, such as mitochondria
  3. Endocytosis -lysosomes digest proteins coming from the cell surface

Like a factory, a cell also produces debris and some of its parts (cellular structures) need to be recycled. Lysosomes release the enzymes on activation by intracellular environmental cues. And also very important, during a certain stage of development lysosomes become very active and digest cellular components by autophagy.

Autophagy (macroautophagy) is an evolutionarily conserved catabolic process (breaking down larger substances and release of energy) representing the cellular degradative pathway in mammals.

Image taken from Quia

Autophagy has been directly connected with anti-aging. “Genetic inhibition of autophagy induces degenerative changes in mammalian tissues that resemble those associated with aging, and normal and pathological aging are often associated with a reduced autophagic potential“. Rubinsztein et al., “Autophagy and Aging“, Cell, Sep 2011

Now, in a paper published recently published online, Oct 2015: Xiaofeng Wang, Huabing Qi, Quan Wang, Ying Zhu, Xianxing Wang, Min Jin, Qiaoyan Tan, Qizhao Huang, Wei Xu, Xiaogang Li, Liang Kuang, Yubing Tang, Xiaolan Du, Di Chen & Lin Chen (2015): FGFR3/Fibroblast Growth Factor Receptor 3 Inhibits Autophagy through Decreasing the ATG12–ATG5 Conjugate, Leading to the Delay of Cartilage Development in Achondroplasia, Autophagy, DOI: 10.1080/15548627.2015.1091551

The authors suggest:

  1. Impaired autophagy in chondrocytes will result in abnormal cartilage development. However, the role of autophagy in achondroplasia is not well understood.
  2. FGF signaling may inhibit autophagic activity in chondrocytes, which may be involved in the pathogenesis of achondroplasia.
  3. Activated-FGFR3 signaling inhibits autophagic activity by decreasing the protein level of ATG12–ATG5 conjugate in chondrocytes, which may play an essential role in the pathogenesis of FGFR3-related skeletal dysplasia.

The team demonstrated that “…the ATG12–ATG5 conjugate was essential for the viability and differentiation of chondrocytes“.

In conclusion:

“Taken together, our studies demonstrate that impaired autophagy is involved in the pathogenesis of achondroplasia. FGFR3 negatively regulates autophagic activity by suppressing the expression of ATG12–ATG5 conjugate. Enhancing the activity of the ATG12–ATG5 conjugate can partially relieve the inhibition of hyperactivated FGFR3 signaling on chondrocyte viability and differentiation. Our studies provide novel insights into the understanding of the mechanisms of FGFR3-related chondrodysplasia and chondrogenesis”.

This can be a future approach for achondroplasia: increasing the ATG12-ATG5 conjugate in chondrocytes. Lets see where this research team can lead these new studies.

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