Evidence for alpha-2-macroglobulin as an orthobiologic osteoarthritis therapy: a narrative review

Orthobiologics rich in alpha-2-macroglobulin (A2M) are being used with increasing frequency to treat equine and human osteoarthritis (OA). The glycoprotein is concentrated from whole blood, typically prepared by a commercial device, and is administered IA with the goal of ameliorating inflammation and associated pain. In recent years, numerous investigations have elucidated A2M's mechanism of action and its effects on joint cells; however, none have used the horse as a model nor have they investigated the commercially available kit for equine orthobiologic preparation, Alpha2EQ. This narrative review presents the most pertinent work on A2M, which supports its current clinical use as an OA treatment. Alpha-2-macroglobulin has been studied in a variety of preclinical models, in vivo, and in clinical patients. As a naturally occurring and potent protease inhibitor, A2M acts to regulate key components of the OA inflammatory cascade, from cytokines and chemokines, which propagate synovitis, to disintegrins and metalloproteinases that degrade the cartilage extracellular matrix. Three main mechanisms of action contribute to A2M's modulation of joint inflammation and concomitant OA progression across species: the bait-and-trap mechanism, direct binding interactions, and regulation of gene expression. In vivo, A2M treatment results in improved histopathology scores, gait improvement in animals, and improved patient-reported outcomes in people. Though substantial evidence exists for A2M's anti-inflammatory effects and role in OA treatment, further studies will be required to elucidate the mechanisms of the equine orthobiologic.