We already have had one very interesting statement to be up there in lights at OARSI, namely:
But tonight, how about an equally amazing read...I'm not talking about distinct symptomatic relief...I'm talking REPAIR.
In the above article, the researchers start of by commenting that Intervertebral disc (IVD) degeneration is a major cause of back pain and plays a pivotal role in terms of socioeconomic impact on affected availabilities as well as on the terms of years living with a disability.
There is currently no therapy available to effectively address IVD. The researchers suggest that the advent of stem cells could possibly assist here. However, it is their findings of what PPS can do in combo with stem cells that has real ramifications for us as investors.
BACKGROUND Stem cells are cells that are not specialised but give rise to more cells of the same type and from which other new cells can arise by differentiations.
*Blah*
Mozz Speak
® Please...
Ahh that's an easy one...they are base like cells and they can spawn off specialised cells that have very particular roles and characteristics, here are some examples:
5 However, In order for stem cells to apply their regenerative properties there is one big hurdle for them that stands in their way....
What is that hurdle......?
I'll give you a hint...
It starts with a capital
...Inflammation.
What do YOU and I know of, that down regulates inflammation?
But remember, we don't want total shut down...we don't want total blocking, we want to address it at the source, in effect we want to down regulate it so the body can STOP going deaf and mad with the constant (chronic) inflammatory ALARMS and signalling....and can get that balance back so the body can finally START working on the restorative, the repair process.....
Stop the incessant (chronic) overly-loud alarm bells of inflammation! But how? Blocking them out totally will cease to alert us of the ongoing destruction! As the researchers comment:
A major obstacle to successful tissue repair is suppressing the inflammatory milieu that exists within the degenerate IVD into which stem cells are transplanted (eg, catabolic cytokines, enzymes etc.) and creating a local environment that is conducive to successful repair and regeneration of the IVD. But what excites me here is this is what they have to say about the combination of PPS and stem cells....it's a potent mix:
Evidence from cartilage repair studies indicates Pentosan polysulfate (PPS) has a number of beneficial attributes in this regard. MORE WAYS We all reading this today should by now have a great sense of how iPPS doesn't just act in
one way.
To tackle an all encompassing progressive disease of the joint tissues and pathologies, you can't throw a single targeting drug at it and hope to reduce pain, increase function and have any remotely disease altering properties! You need the full works...you need direct action and indirect action which we have covered off some of these in the past....someone now please add the following to our ever growing list:
Impact of PPS on serum proteinase inhibitory proteins, coagulation, and the protection of tissues
PPS effects in stressed articular cartilage: effects on molecular signalling - There is an entire couple of Mozz posts to be one day published just on signalling. How iPPS effects this and what it has to do with addressing OA.
PPS regulates chondrocyte degradative proteases and development of OA.
Stimulatory properties of PPS on chondrocytes and production of ECM components
Yes we recently covered the ECM a few weeks ago but I'm seeing the mentioning of more than just TIMP 3 in this article (see main ref below):
"
PPS stimulates PG synthesis by bovine and ovine chondrocytes cultured in the presence or absence of IL-1, and also stimulates HA production by cultured RA and OA synoviocytes..." "...significant reductions in active stromelysin levels and increased levels of TIMP-1, TIMP-2, and TIMP-3 were eviden t".
PPS is a potent inhibitor of human granulocyte elastase and cathepsin-G, cathepsin B1, testicular and arterial hyaluronidase, nuclear heparanase, lysosomal chondroitin-4-sulfatases, and N-acetylglucosaminidase.
Bioactivity of nuclear PPS: potential roles for PPS in the inhibition of nuclear heparanase, regulation of chromatin structure/transcription factor activity, and gene regulation
Certainly I need more time to explore the above but the article suggests that iPPS plays a role within the very nucleus of a cell, we have seen this inference in PAR's own video.(New to us? Do check this wonderful short video to explain a bit more about the biology behind our molecule).
VIDEO Now don't get me wrong here, reduction of symptoms is not only nice, we NEED it to be eligible for some really meaningful and important discussions with the authorities...but the real magic comes from any REPAIR like properties. That's enough to really get people talking ...but the Mozz Clincher?
Well it's another word that starts with R....
REGENERATION Par-folks, I've been following this story intently for the last 4 years...I was an investor back at IPO in 2015 but a very passive one for the first 4 years. I'm still today uncovering magic from what our juice can do. What we have witnessed so far is wonderful...pain reduction, function increase that lasts for a good amount of time (duration effects)...and all in a safe manner...but it's one thing symptomatically to have a drug that works...it's a totally different and novel aspect when we talk about repair and regeneration!
How about this statement from a different study:
6 Pentosan polysulfate binds to STRO-1+ mesenchymal progenitor cells, is internalized, and modifies gene expression: a novel approach of pre-programing stem cells for therapeutic application requiring their chondrogenesis .
Yeah we need some interpretation.
I won't make it a science fest but at a high level, these researchers wanted to see the effect on PPS in terms of proliferation and chondrogenesis of the MPC cells.
MPC cells were taken from human bone marrow and cultured and then PPS was added (the MPC culture was primed) and analysed.
I give you the conclusion:
This study has shown that priming of MPCs with low concentrations of PPS enhanced chondrogenesis and MPC proliferation by modifying their characteristic basal gene and protein expression. These findings offer a novel approach to re-programming mesenchymal stem cells for clinical indications which require the repair or regeneration of cartilaginous tissues such as in osteoarthritis and degenerative disc disease. More evidence is obtained by another study in which PPS was added to MPC cells as well as SCAF (Gelatin/fibrin scaffold). Some
66% of histological sections of the treated discs exhibited less degeneration than the other discs! Their conclusion was also quite a read:
7 These findings demonstrate the capacity of MPCs in combination with PPS, when embedded in a gelatin sponge and sealed with fibrin glue in a microdiscectomy defect, to restore disc height, disc morphology, and nucleus pulposus proteoglycan content. I always enjoy a good graphic, easier to understand what's going on...but first a small primer for those that don't know the science well:
The PG's (Proteoglycan) play 4 vital roles:
Lubricating fluid in the joints. Hydrating cartilage. Participating in cell and tissue development. Controlling blood coagulation. Just check this graphic out:
That's about a 40% increase due to PPS....we want more PG's.
Startling.
What was the p value in the above? p < 0.005
Finally it is their conclusion I close with...I just couldn't articulate it any better than this:
"PPS promotes proliferation and chondrogenic differentiation of adult human bone marrow-derived MSCs, a cell type with exciting tissue repair and regenerative capability and of potential application in IVD repair and regeneration. Overall, PPS has impressive credentials in the promotion of tissue repair and remodelling of damaged connective tissues and now this can be extended to the promotion of IVD tissue regeneration". Symptomatic relief sure, is one thing....repair and regeneration is our future.
Oh, don't forget the DYOR bit.
REFERENCES 1]
https://www.liebertpub.com/doi/10.1089/scd.2022.0007?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed OTHER REFERENCES 2]
https://oaaction.unc.edu/oa-module/oa-prevalence-and-burden/ 3]
https://www.coloradospineinstitute.com/education/anatomy/intervertebral-discs/ 4] https://www.physio-pedia.com/Intervertebral_disc
5] https://www.mayoclinic.org/tests-procedures/bone-marrow-transplant/in-depth/stem-cells/art-20048117
6]
https://pubmed.ncbi.nlm.nih.gov/29237492/ 7]
https://pubmed.ncbi.nlm.nih.gov/24702507/ 8]
https://www.merriam-webster.com/medical/fibrocartilage 9] https://www.carexpert.com.au/car-news/adaptive-suspension-explained#gallery-6
10] https://study.com/academy/lesson/proteoglycans-definition-function-structure.html#:~:text=Proteoglycan%20Function,-Proteoglycan%20function%20includes&text=Lubricating%20fluid%20in%20the%20joints,Controlling%20blood%20coagulation
Not sure how many bother to read to this point but if you are one of them...
(20min delay)