Alpha-2-Macroglobulin (a2-M or A2M)

A truly remarkable substance

A2M is a remarkable substance with ample evidence for its effectiveness in treating osteoarthritis (OA) and degenerative musculoskeletal conditions like tendinosis and tendon tears. We now know that a major culprit in these diseases is enzymes (proteases) that destroy structural proteins such as collagen, leading to cartilage, tendons, ligaments, and bone breakdown. A 1999 study showed that in chronic wounds, proteases are present in abundance and are responsible for failure to heal.1 In short, proteases in high concentrations, which is a typical scenario for chronic tissue damage and joint disease, are bad. A2M binds these enzymes in a manner similar to a venus fly trap and carries them away for disposal, making it an ideal substance for stopping disease processes in OA, chronic non-healing injuries, and tendon or ligament disorders.2 The goal of treatment is not to suppress symptoms but rather to stop tissue destruction. This represents a significant departure from standard approaches, which use pain medications and cortisone, none of which are disease-modifying.

A2M is a game changer in the treatment of musculoskeletal conditions

Using an FDA-compliant sterile device, we obtain A2M in a concentrated form, 80 to 100 times baseline concentration, from your blood plasma. Using precise ultrasound guidance, the A2M is delivered to the location of the disease, whether it be a joint, an area of degenerated and torn tendon, or a damaged ligament. Platelet-rich plasma (PRP) is injected with the A2M to provide growth factors for healing. We have seen improvement using A2M plus PRP is substantially faster than with PRP alone or with PRP and lipoaspirate (your own fat). As a result, activity and sports downtime is reduced, return to play quicker, and pain relief occurs sooner. In addition, with ultrasound, we see restoration of the integrity of tendons and ligaments within weeks.

Some of the destructive enzymes that A2M traps include:

1. ADAMTS-7 and ADAMTS-12, which destroy cartilage oligomatrix protein (COMP)³
2. Matrix Metalloproteinase-3 (MMP-3), which is one of the first MMPs to be activated in the OA process and activates other MMPs.⁴  MMP-3 is a particularly bad player.  A2M binds a wide variety of MMPs.
3. ADAMTS-4 and ADAMTS-5, which destroy glycosaminoglycans (GAGs) within cartilage.⁵ GAGs are essential for cartilage strength, and their loss renders the cartilage susceptible to damage from activity.

Dr. Adams instrumental as senior researcher

Dr. Adams was the senior researcher on a study of osteoarthritis in Montana ranchers, which demonstrated a correlation between worse joint symptoms during calving season and elevated MMP-1 levels.  The study also found that ranchers with a higher body mass index had higher MMP-3 levels.⁶

1. Yager DR, Nwomeh BC. The proteolytic environment of chronic wounds. Wound Repair and Regeneration 1999;7(6):409-527.
2. Scuderi, G.J., Hanna, L. (2018). Alpha-2-Macroglobulin: Protease Inhibitor Treatment (PRP Variant). In: Diwan, S., Deer, T. (eds) Advanced Procedures for Pain Management. Springer, Cham. https://doi.org/10.1007/978-3-319-68841-1_39
3. Luan Y, Kong L, Howell DR et al. Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. Osteoarthritis and Cartilage 2008;16(11):1413-1420.
4. Bedi A, Kovacevic D, Hettrich C et al. The effect of matrix metalloproteinase inhibition on tendon-to-bone healing in a rotator cuff repair model. J Shoulder Elbow Surg 2010;19(3):384-391. – This study in rats not only demonstrates MMP inhibition by A2M, but also improved rotator cuff tendon healing in their experimental model.
5. Tortorella MD, Arner EC, Hills R, Wittwer AJ, Liu R-Q, Malfait A-M. α₂-Macroglobulin is a novel substrate for ADAMTS-4 and ADMTS-5 and represents an endogenous inhibitor of these enzymes. Enzyme Catalysis Regulation 2004;279(17):P17554-17561.
6. Thompson MA, Martin SA, Hislop BD, Younkin R, Andrews TM, Miller K, June RK, Adams ES. Sex-specific effects of calving season on joint health and biomarkers in Montana ranchers. BMC Musculoskel Disord 2023;24(1):80.  doi: 10.1186/s12891-022-05979-2   PMCID: PMC9887842