Alpha-2-Macroglobin is a plasma protein found in the blood. It is produced in the liver but can also be synthesized by macrophages and fibroblasts.
A2M functions as an antiprotease and inactivates these enzymes.
Protease is an enzyme that catalyzes proteolysis, which is the breaking down of larger proteins into smaller polypeptides for new formations. This action can either be normal or abnormal.
Matrix metalloproteinases are inflammatory mediators that degrade various components of the Extra cellular matrix and non –ECM mediating tissue remodeling in both physiological and pathological processes.
MMP are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis synovial fibroblasts produce matrix degrading enzymes, including MMP’s, which facilitate cartilage destruction in the affected joints in RA.
MMP’s are enzymes that have the ability to break down connective tissue.
These enzymes are increased in various pathological conditions where inflammation is present such as osteoarthritis and RA.
Alpha 2 Macroglobulin is a protease inhibitor which inhibits activated MMP’s. The A2M forms a complex with the MMP and blocks its function.
By definition, an enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions. The reactions provide substrate molecules which are then converted into other products. These products can be necessary to the organism or pathological.
How alpha macroglobulins work
- The entire class of macroglobulins have the ability to inhibit proteases from all catalytic classes
- Presence of a “bait region” which is a specific sequence of amino acids, which contains peptide bonds for the proteases that it inhibits. This bait and trap mechanism is the main way A2M cleaves to the proteinases.
- The complex of the A2M and proteinases is chemically inert and then can be bound to clearance receptors to be removed from the circulation.
J Orthop Res 2023 Jan;41(1): 241-248 PMID 35451533
A hallmark of osteoarthritis is cartilage degeneration with dramatic increases in inflammatory enzymes. Interleukin-1B (IL-1B) and the upregulation of nuclear factor kappa B (NF-kB) are both implicated in post- traumatic osteoarthritis. Alpha 2 macroglobulin can inhibit this inflammatory pathway.
In a study aimed to demonstrate the action of A2M, the authors created an inflammatory environment and then treated it with A2M. The degree of binding between A2M and IL-1B was then evaluated. This experiment demonstrated that A2M could bind IL-1B. Additionally, A2M neutralized Il-1B and NF-kB. A2M also decreased the levels of MMPs and TNF-alpha and increased cartilage protective genes. The results demonstrate A2M reduces catabolic activity and increases protection for future joint arthritic activity.
Phys Med Rehabil Clin N Amer 2016 Nov;27(4): 909-918 PMID 27788907
A2M is a plasma glycoprotein best known for its ability to inhibit a broad spectrum of metalloproteases as well as inflammatory cytokines by a unique bait and trap method. A2M has emerged as a unique potential treatment of cartilage- based pathology and inflammatory arthritides. This article describes the unique method by which A2M not only inhibits the associated inflammatory cascade but also disrupts the catabolic process of cartilage degeneration.
Both A2M and Platelet Rich Plasma are autologous blood derived products. A2M is present in PRP concentrates but not at the higher levels that can be obtained using a commercial kit specifically made for the purpose of extracting A2M alone.
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