would always like to start a new year with a bang. Maybe I'm...

would always like to start a new year with a bang. Maybe I'm talking fireworks...but maybe even more appropriately, I'm talking about a Mozz Post.

Can't tell you what a joy it was to research this one and type it up. I learnt a lot researching this one, I hope you do too, strap yourself in, grab your favourite drink/snack, this will be just quite a read.

Oh and before we get stuck into it, If the science gets a bit much for you, skim read the details in Parts 1 and 2 but don't miss the Mozz (Please spoon feed me) Exec. Summary towards the end of Part 2, this will wrap up the two parts in just a few dot points. This is the take away that I'd like to leave you with.

For Major Post number one for 2025, I'm trying a new format just for this one post. Think of it as a Question and Answer style post.

Please as always, do now enjoy



PART 1 HYALURONIC ACID


WHAT IS HYALURONIC ACID?

Well here is a techy type answer:


"Hyaluronic acid (HA) is a naturally occurring non-sulfated glycosaminoglycan (GAG) non-protein compound with distinct physico-chemical properties of repeating β-1,4-D-glucuronic acid and β-1,3-N-acetylglucosamine units".

"HA has excellent viscoelasticity, high moisture retention capacity, high biocompatibility, and hygroscopic properties. At a concentration as low as 0.1%, HA chains can provide high viscosity". ¹

"HA has an important role in the biomechanics of normal SF, where it is partially responsible for lubrication and viscoelasticity of the SF". ²


HA - My second favourite molecule. A gooey clear substance...what a molecule! Read on for further details!








MOZZ FACT


Hyaluronic acid is very good at retaining water. A quarter-teaspoon of hyaluronic acid holds about one and a half gallons of water (5.6 litres!) .³






HOW MUCH HA DO WE TYPICALLY HAVE?

A person with an average weight of 70 kg has about 15 g of HA.



WHERE IS IT LOCATED?

HA is present pretty much all over but predominantly in the joints, skin, eyes and other organs and tissue of the body.



WHAT IS THE TURNOVER RATE?

5 g turns over daily



WHERE IS THE GREATEST AMOUNT IN THE BODY?


The greatest amount of HA is present in the skin (about half of the total HA, synovial fluid, the vitreous body , and the umbilical cord.


WHAT DOES HA ACTUALLY DO?

HA acts as a lubricant, shock absorber, joint structure stabilizer, and water balance and flow resistance-regulator.

Physiological roles of HA are well-characterized in body tissues and fluids. In general, HA may be involved in various cellular interactions (cell differentiation, proliferation, development, and recognition) and physiological functions (lubrication, hydration balance, matrix structure, and steric interactions).

But don't for an instance think this is like a passive humectant, holding huge amounts of water (compared to the weight of itself)...it is much more active and has far reaching functions and roles.Yeah this is one super molecule.

"HA is an important constituent of the ExtraCellular Matrix (ECM)".


Mozz Speak? This is like the pool of nutrients in-between and amongst cells that cells can draw upon. HA contributes to cell proliferation, migration, and morphogenesis.

"HA also occurs within cells and it has been reported to have roles inside the cell. Within the joint cavity, HA molecules are predominantly synthesized by type B synoviocytes". ¹


The physiological relevance of HA is not only recognized in healthy and OA joints, but also in other tissues and health conditions

HA also plays a role in wound repair.

"...it’s effective at reducing gum disease, speeding up healing after tooth surgery, and eliminating ulcers when used topically in the mouth". ⁴


Wound repair..


We also know it plays a major role in connective tissues.


"Hyaluronic acid is also found in the joints, where it keeps the space between your bones lubricated". ⁴


Are you starting to get a sense of where I am going with this one? It is a critical molecule...but how does one produce this, not by injecting it exogenously, from outside the body like via injection...I want my own cells to produce the Higher weighted blend NATURALLY.

Helloooo iPPS.


ARE HA MOLECULES LARGE AND/OR COMPLEX?

Oh how about a Mozz Quiz, first one and definitely not the last one for 2025?


HOW MANY CHAINS (DISACCHARIDE REPEATS) ARE THERE IN A TYPICAL HA MOLECULE?



A) 48, that sounds about right?




B) Nah..think bigger....go for it....200 ??






C) 1000?







Well the answer here is 25,000. These are long chains!


"HA (a polymer of disaccharides) can be 25,000 disaccharide repeats in length with a MW of 5,000–20,000,000 Da". ¹



HOW IS IT DELIVERED/DISTRIBUTED ?


"Balogh et al. also noted that the appearance of radioactivity in tissues before blood suggested that HA was delivered to tissues via a non-blood transport system. Lymphatic uptake and transport could explain these findings. It is also known that transport of higher-MW HA into and out of synovial spaces occurs via lymphatics and its normal presence in blood and other fluids provides mechanistic support for the appearance of ingested HA in connective tissues". ¹



HOW IS IT REMOVED FROM THE BODY?

Findings revealed that the liver removes ~90% of the circulating HA and the remainder is removed by the spleen


SO, WHAT IS THE PROBLEM?

HA is catabolized by hyaluronidases, and the Molecular weight (MW) of HA in cartilage is reported to decrease with age. Yes Paradigmers, as we age, we lose that lovely higher weighted blend of HA and we get more of the lower weighted variety. *sad face*



I want HWHA !!! Pppssst are you new to iPPS and PAR? How about a secret (you can also read this further down in this post, but iPPS is one of the key ways to produce HWHA...it does it NATURALLY!


"In late-stage OA, the cartilage becomes hypocellular, often accompanied by lacunar emptying, which has been considered as evidence that chondrocyte death is a central feature in OA progression. Chondroptosis is also characterized by increases in caspase-3 and−8, DNA fragmentation, increases in MMPs and ADAMTS, and decreases in aggrecan and type II collagen. It remains unclear whether chondroptosis is a cause or consequence of cartilage degeneration in OA".


"OA is characterized by the degradation of cartilage matrix components (including cartilage-specific type II collagen and the PG aggrecan), resulting in the loss of cartilage structure and function (42, 43, 141). ECM loss occurs due to elevated enzyme (collagenases, aggrecanases, and MMPs) activity. Chondrocyte death and ECM loss may form a vicious cycle, with the progression of one aggravating the other, and there appears to be a correlation between the degree of cartilage damage and chondroptosis.Reversal of some of these mechanisms (as described above) provides the rationale for the use HA in OA".


OA is typified by Chondrocyte death and degradation of the ECM. You do not want to see this occur.


For the readers that have been following me for years, YOU know that MMPs and ADAMTS are bad, we want these controlled! Yes PAR has findings on these specifically. Here is just one example ⁵ in terms of what iPPS's effect is on this OA Biomarker known as COMP and ADAMTS-5:



Phase II results - Paradigm Biopharma.


When looking at the above, please remember our n back then was a paltry 56. We still achieved a decent p value of 0.03. What will this be when n bumps up to 233? As if that's not enough, placebo went the other way and continued to degrade.


"In OA, synovial HA is depolymerized (MW, 2,700–4,500 kDa) and cleared at higher rates (11–12 h) than normal ". ⁶

So what we want is the maintenance of the molecular weight of HA, which left on its own device, will deplete and degrade over time...

However, we don't just want more of any ol' HA...we want the good stuff, and indeed we get it via iPPS:

"In vivo studies have demonstrated the ability of intra-articular PPS to stimulate the synthesis of hyaluronan with increased chain length in RA affected joints". ⁶

...and further...

"The M [Aver Molecular Weight] of hyaluronan in air pouches treated with PPS (1.39 • 0.72 x 106) was significantly greater (P < 0.05)than that in non-drug-treated controls".



THE NEGATIVE EFFECT OF CORTICOSTEROIDS

I knew Corticosteroids. are great for pain relief, take this shot and you will most likely get 3 lovely months of sheer pain relief before the pain starts coming back. Those simple three months of relief could be costly. Corticosteroids damage the cartilage. Perhaps one injection might be fine...but cumulatively....caveat emptor - buyer beware!


But while researching this very topic on HA, i discovered the reason why Corticosteroids is also so damaging.



WHY ARE CORTICOSTEROIDS SO DAMAGING?

I give you one quote:


"Treatment with corticosteroids reduces the serum HYA level". ⁷

...but also...

"...at higher doses (>3 mg/dose or 18-24 mg/cumulative total dose in vivo), corticosteroids were associated with significant gross cartilage damage and chondrocyte toxicity". ⁸

...This extract from the Arthritis Foundation of America. ⁹


(Single left click above to enlarge).




OILS-AIN'T OILS - SO HA IS A PASSIVE LUBRICANT?


The old Oils ain't Oils ad...Apt for us!


Well no, it's versatile, here is another example of its proactiveness. Mozz Note: Here is a brand new learning for me...I'll explain after the quote.

"HA binds to ECM molecules and cell surface receptors, thereby regulating cellular behavior via control of the tissue's macro- and micro-environments".


I did not know that the HA molecule itself binds to the cell surface receptor...it literally surrounds the cell to assist in positive cellular behaviour. Are you guys getting a sense of this molecule's utility?


""Aviad and Houpt suggested that the beneficial effect of injected HA in joint disease, such as OA, may be due to pharmacological effects rather than to physico-chemical properties (such as SF viscosity, HA concentration, HA MW, and the rate of synthesis). Taken together, findings suggest that the beneficial effects of HA may be due to both rheological properties and pharmacological mechanisms".


"Because OA affects a limited number of joints (such as shoulder, elbow, stifle, hip, hands and feet), local treatment, such as an IA HA delivery system, has been reported to be of paramount importance".


I've covered the production of Nitric Oxide before (NO) which has a role in OA. Again, quite sciency but take a read of this one:

"It is well-established that oxidative/nitrosative stress and inflammation are involved in OA-cartilage degeneration. In surgically-induced OA in New Zealand white rabbits, Takahashi et al. (65) found that the amount of nitric oxide (NO) produced by the meniscus was much greater than that produced by the synovium. Also, NO production in the meniscus and synovium of the HA group were significantly lower than those without HA treatment. The results suggested that the inhibition of NO production in meniscus and synovium might be a part of the mechanism of the therapeutic effect of HA on OA. In addition to NO, superoxide and hydroxyl radicals are also reported to be involved in the pathogenesis of OA, and their levels are reduced by HA treatment".


Our own P Ghosh also observed production of HA due to iPPS:

"Moreover, synoviocyte biosynthesis of high-molecular-weight hyaluronan, which is diminished in OA, was normalized when these cells were incubated with NaPPS and CaPPS or after intraarticular injection of NaPPS into arthritic joints. In rabbit, canine, and ovine models of OA, NaPPS and CaPPS preserved cartilage integrity, proteoglycan synthesis, and reduced matrix metalloproteinase activity". ¹⁰



ONE TRIGGERS ANOTHER

Hmm ok for this one we need some background first.

What exactly is an MMP anyway?
I have covered this in the past but a refresher:

MMPS's stands for matrix metalloproteinases. These are evil. Why? Cos they destroy proteoglycans, collagens and other ECM molecules. ¹¹

Remember, I think of the ECM as the Shell shop on the country highway...a place to refuel, nourish up and derive benefit. Kinda like the cells in the pool of the ECM. Destroy a country petrol station and you may not have any fuel for the next x hundred of kilometres.


ECM?


Speaking of cars...It's a bit like an airbag in your car.





What has this to do with Pentosan???


When you emergency break the first sensor fires off a chemical reaction that ignites and result in the deployment of an airbag. However, if that were all that worked, you'd be dead. What do I mean? Well you hitting any part of that inflated airbag is like you hitting a wall. So as soon as that first chemical reaction is deployed a second chemical reaction is instantaneously deployed to DEFLATE the airbag so in actuality is becomes a real cushion and absorbs your impact with it.

It's the same way with this HA molecule. iPPS triggers the HWHA molecule and that in turn it also has many wonderful and positive effects.

Now you have the required background to read the next bit, remember IA = Intra-articular, SF = Synovial Fluid.



In an in vitro study, Sasaki et al. demonstrated that the expression of MMP-1 and MMP-3 mRNAs were induced by IL-1β in human synovial cells, and were strongly downregulated by HA (10 or 1,000 μg/mL). HA may inhibit binding of IL-1β to its membrane bound receptor by covering the cell surface, thereby suppressing the production of MMPs. The study suggested that IA HA may rescue inflamed joints from bone and cartilage destruction by reducing the production of MMP-1 and MMP-3. Yasui et al. reported suppression of IL-1α-induced PGE2 production in human synovial cells by HA in a dose- and MW-dependent manner. In another in vitro study, Maneiro et al. investigated the effects of two HA formulations (Hyalgan®, 500–730 kDa HA, Bioibérica SA; and Synvisc®, hylan of 6,000 kDa, Biomatrix Inc.) on PGE2 and NO concentrations and in human OA chondroptosis. Results revealed that 500–730 kDa HA (200 μg/ml) decreased the synthesis of both IL-1-induced PGE2 and NO by 70 and 45%, respectively. Both HA preparations at 200 μg/mL decreased chondroptosis (40 and 36%, respectively). HA has also been reported to protect against hydroxyl (OH) radicals generation. It has been demonstrated that by modulating rheological properties (such as viscoelasticity) of HA and SF by employing HA of selective MW or HA-derivatives, anti-inflammatory activity can be greatly improved.




"Higher-MW HA (Synvisc) provided the greatest ability to inhibit MMP-2, MMP-9, u-PA and PAI-1 expression. Findings clearly demonstrated that the therapeutic effects of using higher-MW HA to treat early OA may be partially dependent on downregulation of the PA/plasmin system and MMPs expression, which delay the structural progression of OA".

I love the use of that word 'clearly'...as well as downregulation. Delay of structural progression of OA does it for me.

I think that's a great place to stop, pause, reset and reflect.
.

That rounds out Part 1. In Part 2 we go further into what this molecule HA is capable of.



Oh let me tease you into Part 2.


Watch out for two pieces; an executive summary specially for those that get a bit lost in the science....but also I will give you not one but two practical stories. These are the stories that i personally use to translate theory to investment thesis.