I say try because there is a lot of scientific content in this paper, a lot of stuff that I have not done in the lab before and this makes it harder for me to work out exactly what it means, I will however try my best to understand it and where possible try and explain it in as simple terms as possible.
To start with for those who don't know Xiaflex is a treatment for Dupuytren's disease (DD) and potentially Ledderhose disease (LD), it is a collagenase and the main component of the lumps in DD and LD is collagen and so it breaks them down.
Right onto the paper, where possible I shall try and bullet point it and I am going to place a summary at the end where I will put what I consider to be the key points.
- DD is a common and benign disorder.
- The cause(s) of DD and LD are unknown however DD has been linked to genetics, smoking, diabetes, alcohol, anti-epilepsy medication, occupation and local trauma (so all the usual stuff).
- The group of people at the most risk are Caucasian men of North European descent that are 40 or over with highest incidence in USA, Scandinavia, Britain and Australia.
- The disease shows cell proliferation, high levels of collagen and extra-cellular matrix remodelling.
"Treatment of DD is not curative" and this means that rather than trying to rid the body of the disease they are just trying to remove the symptoms.
One current treatment that is showing promise is Xiaflex which is a collagenase that digest the triple helical structure of collagen and therefore removal the lumps and whilst this is significantly less invasive than surgery it does have a much higher level of recurrence.
Aim: Their aim is to investigate the functional effects of Xiaflex in comparison to Collagenase A when used on cells cultured from DD nodules, cord, fat and skin. They look into various different aspects of the cells including looking at the cell growth and at gene expression.
So I am going to try and go through this and explain the key points one figure at a time to make it easier to follow.
Figure 1: Here they just show the process through which they have derived the cells and then the experiments that they are planning to do on them.
Figure 2 (and Figure 3): Here they are measuring the ability of the cells from the DD nodules and cords to grow in the presence of Xiaflex / Collagenase A and whether they are able to recover from this treatment in 24 hours by removing the drug and continuing to monitor the cells. In Figure 3: They also look at fat and skin cells from DD patients in a similar way.
- They find that without treatment there is no significant different between the nodules and cords compared to the skin and fat although the DD nodules and cords do show a faster growth rate. This makes sense as it is a proliferative disease.
- Treatment with Xiaflex / Collagenase A decreases all of the things that they are measuring in ALL cell types in a dose dependent manner.
- 24 hours after removal of the drug the cells recover, this happens even at the highest dose and may help to explain why DD comes back so frequently when treated with Xiaflex.
|The central dogma: DNA is where the information is stored and this is processed into RNA and then proteins.|
- They are looking in DD disease and see that Xiaflex treatment causes a decrease in levels of collagen I and collagen III as well as fibronectin (forms part of ECM and interacts with collagen), alpha SMA and TGF-B1. If you remember from my previous post a decrease in TGFB1 would be useful. Explained in the image below.
|Central blue boxes show state in DD cells, right hand side is reported influence of Xiapex in DD cells|
- They also say that levels of collagen are at their highest in the DD nodule which is exactly what you would expect.
- They show that the levels of Collagen I and III in the nodules are very high with Collagen III in particular very, very high (basically two times more than seen in anywhere else).
- When looking at the effects of Xiaflex and Collagenase A they see that:
- Collagenase A has an influence on Collagen I by causing a decrease on all samples at the highest dose only.
- Collagenase A only decreases Collagen III at the highest 2 doses in the nodules, cords and fat.
- Xiaflex causes a large decrease on all samples at all doses for both Collagen I & III with the largest decrease observed in the Nodules and cords.
- Xiaflex does down regulate the protein levels of fibronectin, Collagen and CTGF (and more) at the protein level.
- DD nodules and cords do show a faster growth rate.
- Xiaflex and collagenase A both decrease the growth rate in DD cells.
- Xiaflex treatment causes a decrease in levels of collagen I and collagen III as well as fibronectin and TGF-B1 (see the diagram as to why this might be good).
- Levels of Collagen I and III in the DD nodules.
Syed F, Thomas AN, Singh S, Kolluru V, Emeigh Hart SG, et al. (2012) In Vitro Study of Novel Collagenase (XIAFLEX®) on Dupuytren's Disease Fibroblasts Displays Unique Drug Related Properties. PLoS ONE 7(2): e31430. doi:10.1371/journal.pone.0031430