A2M

alpha-2-macroglobulin Alpha-2-macroglobulin (A2M) is the biologic treatment for your arthritic knee that you are carrying around in your own bloodstream! Your body creates a very large protein in your liver which is carried via your bloodstream to your various organs and has several important roles to keep you healthy. The protein is called alpha-2-macroglobulin (A2M) and is among the largest and heaviest proteins that your body makes. It is a naturally occurring plasma glycoprotein whose principal activity is to counteract the protein/enzymes called proteases that breakdown various chemicals and molecules no longer needed in your body in a well-balanced chain of events that keeps you healthy.

 

In a tremendous breakthrough, scientists at EmCyte have discovered that this very large protein can capture and neutralize the proteases created in an arthritic joint that cause the destruction of the articular cartilage. By reducing these destructive substances, it effectively halts the progressive damage seen and felt in the osteoarthritic joint. For those of us involved in the care of the arthritic patient, this is really a huge advancement!

Severe OA in knee at surgery.
Complete destruction of articular cartilage.

Before explaining this treatment further, let’s first put the problem of osteoarthritis (OA) into perspective. The Australian National Centre for Disease Control estimates that some 2.5 million adult Australians are afflicted with osteoarthritis. Furthermore, it is estimated that 1 in 3 adults will get symptomatic knee osteoarthritis in their lifetime. With the combination of the ageing Baby Boomer population, increased longevity of the general population and the fact that obesity is now a health issue, the rising prevalence of OA is expected to contribute even more heavily to the severe health and economic effects already present. Osteoarthritis often causes weakness and disability, interferes with work productivity, and often ultimately results in joint replacement.

Disappointingly, we currently only have treatments that try to alleviate the pain symptoms of osteoarthritis…..NSAIDS, aspirin, Advil, cortisone injections, viscosupplementation and so on. None of these treatments is actually disease-altering or what we would think of as a “biologic treatment” of osteoarthritis. In addition, we encourage weight loss, exercise and activity modifications to deal with the fluctuation of arthritic pain that occurs in our joints.

What we have not had available so far is a true biologic treatment that alters the course of eventual destruction of the arthritic joint.  A treatment that actually halts the progression of deterioration of the articular cartilage, which when finally worn completely away leaves us with little to do but to consider a surgical solution such as joint replacement surgery. What we have been looking for is a true biologic treatment of osteoarthritis that effectively stops the deterioration of the joint. A consideration in the treatment of arthritis is in alpha-2-macroglobulin.

Cellular biology of osteoarthritis,  is necessary to understand, at least superficially, the process of osteoarthritis which, as we in the scientific field understand, involves a process of “turning on” or up-regulation of various catabolic (destructive) and inflammatory proteins called proteases. This up-regulation process results in a massive production of these highly destructive proteases which directly damage the articular cartilage. How the destructive process is “turned on” remains unsolved, but the collection of these proteases, including cytokines and matrix metalloproteinases, are intensely destructive and over time, if unchecked, will lead to the loss of the protective cartilage covering of the joint and the development of significant and limiting joint pain.

a2m
A2M has two binding sites to which proteases (E) are captured. This interaction permanently changes the shape of the A2M and creates a condition where the complex can now be broken down and eliminated by the body through natural mechanisms.

Circling back, scientists have made the connection that A2M has unique and almost miraculous properties, which include a powerful inhibition of cartilage catabolic and inflammatory proteases effectively neutralising the process that leads to osteoarthritic cartilage degradation and joint destruction1, 2.  In other words, it stops arthritis in its track!

In addition, another recent study from Brown University has tagged this protein as a “Master Inhibitor” of cartilage-degrading enzymes and proved that it acts not only by blocking activity of the destructive proteases, it actually suppresses gene expression that leads to elevated protease levels in the joint3.  The conclusion of this study was that A2M is chondroprotective if present in high enough quantity.

Therefore, it has been inferred that supplemental intra-articular injections of alpha-2-macroglobulin diminishes cartilage degeneration and may be a potential therapy for osteoarthritis. In short, if it was possible to get more of this protein into an arthritic joint early in the arthritic destructive process, it is quite possible to at least slow, if not halt, the progression of joint deterioration3, 4.

The liver manufactures a significant quantity of alpha-2-macroglobulin and it circulates in your blood stream in a large quantity. Recent studies have shown that A2M is a molecule, unable to cross the synovial membrane into the joint in sufficient quantities to effectively neutralise the destructive catabolic proteins that have been up-regulated (“turned on”) and are ultimately causing the joint to deteriorate.5  If only there was some way to get this miraculous protein from your blood stream into your arthritic knee.  Now that would be a real breakthrough in treating arthritis.

EmCyte have developed a protein plasma concentrator as a method of collecting alpha-2-macroglobulin from the blood stream and then using a relatively simple mechanism of delivering it into your arthritic knee. Just recently, they have perfected a method whereby your own blood is collected and processed with a centrifuge and a proprietary filter which isolates and concentrates your own blood product down to a small portion of highly concentrated A2M that can be directly injected into your knee or any other osteoarthritic joint.

Filtration process to concentrate “A2M” from patient’s blood.

This proprietary process from Emcyte has been named the “Autologous Plasma Protein Concentration System” or “APPC -  PRP” system. It is the only PRP system currently available that concentrates A2M while minimizing platelets, white blood cells and other proteins. Most other PRP systems on the market leave in a high concentration of platelets and white blood cells in their preparations. The “APPC - PRP” system reduces the white cell count in the preparation to negligible levels, thereby, allowing the concentrated alpha-2-macroglobulin to more efficiently neutralise the cytokines and metalloproteinases that are destroying the joint. This proprietary method concentrates the A2M to a level 9 to 10 times the concentration found in the blood stream.4

The EmCyte Plasma Concentrator contains a 7mL concentrating chamber with microfiber filaments that quickly and accurately removes water from plasma proteins.  This system effectively concentrates all plasma proteins, including albumin, globulins, fibrinogen, regulatory proteins and clotting factors.  A 30mL sample of plasma can be concentrated down to 10mL in less than five minutes without centrifugation.

  • This biologic treatment works best in joints where the destruction has not reached the point of total destruction, or where the joint is “bone on bone.” This is referred to as “end stage arthritis, Grade IV.” A biologic treatment that is designed to help “slow” or “prevent” further destruction will have little effect when the destruction of the articular cartilage has become extreme. This treatment is for the treatment of mild to moderate osteoarthritis.
  • This treatment is not the “platelet rich plasma” or “PRP” concept that has been available through many companies for over a decade and is typically used in the field of regenerative medicine. The “APPC - PRP” system referred to here minimises platelet and white cell concentrations while maximizing the concentration of the desired chondroprotective protein alpha-2-macroglobulin. This is unique in the populated field of PRP systems currently available.

  1. Browning S, et al.; Chondroprotective effect of alpha-2-macroglobulin (A2M) on bovine cartilage explants. Data on file with Cytonics, Corp.
  2. Tortorella MD, et al.; alpha-2-macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes. J Biol Chem 2004; 279:17554-61.
  3. Wang S, et al.; Identification of alpha-2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheum 2014; 66:1843-53.
  4. Cuellar JM, et al.; Is there a chondroprotective effect of autologous protease inhibitor concentrate on an osteoarthritis rabbit model? A pilot study. Data on file at Cytonics, Corp.
  5. Woolley DE, et al.; Small molecular weight ?1 serum protein which specifically inhibits human collagenases. Nature 1976; 261:325-7.
  6. Malavolta EA, et al.; Platelet-rich plasma in rotator cuff repaira prospective randomized study. Am J Sports Med 2014, Aug. Publ online.
  7. Clinical Practice Guidelines on the Treatment of Osteoarthritis (OA) of the Knee (non-arthroplasty)2nd Edition. Adopted by the American Academy of Orthopaedic Surgeons Board of Directors May 18, 2013http://bit.ly/1wtTOAZ
  8. ClinicalTrials.gov. Serum and synovium protease inhibitor levels in primary and secondary osteoarthritic joints. http://clinicaltrials.gov/show/NCT01613833. Accessed Sept. 2014.
  9. Page MR; The age of targeted osteoarthritis therapy begins. Pharmacy Times. Published online, Wed., Sept. 17, 2014. http://www.pharmacytimes.com/news/Alpha-2-Macroglobulin-The-Age-of-Targeted-Therapy-for-Osteoarthritis-Begins