Role of Alpha-2-Microglobulin in the Treatment of Osteoarthritic Knee Pain: a Brief Review of the Literature

  • Vwaire OrhurhuEmail author
  • Ruben Schwartz
  • Jacob Potts
  • Jacqueline Peck
  • Ivan Urits
  • Mariam Salisu Orhurhu
  • Charles Odonkor
  • Omar Viswanath
  • Alan Kaye
  • Jatinder Gill
Hot Topics in Pain and Headache (N. Rosen, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hot Topics in Pain and Headache


Purpose of Review

Chronic knee pain remains a debilitating condition that remains difficult to manage. The purpose of this review, therefore, is to summarize current understanding of alpha-2-microglobulin in the treatment of osteoarthritic knee pain. Furthermore, we investigate its role in the anti-inflammatory properties of platelet-rich plasma (PRP).

Recent Findings

Alpha-2-microglobulin, a 720-kD protein complex, is an active protease inhibitor with tremendous anti-inflammatory properties in animal models. A growing body of evidence suggests that this complex is the most instrumental factor for cartilage preservation in PRP injections.


As an active component of platelet-rich plasma’s anti-inflammatory properties, alpha-2-microglobulin has been shown to be an active inhibitor of joint degeneration, cartilage preservation, and improvement in quality of life for patients with knee osteoarthritis compared with a multitude of other modalities.


Alpha-2-microglobulin Proteinase Platelet-rich plasma Osteoarthritis 


Compliance with Ethics Guidelines

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Holtedahl R. Atraumatic knee pain. Tidsskr Nor Legeforen. 2018;138(5).
  2. 2.
    Arthritis Basics. CDC. Retrieved from 1 Jan 2019.
  3. 3.
    Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a US population-based survey. Arthritis Care Res. 2016;68(5):574–80.CrossRefGoogle Scholar
  4. 4.
    Ourradi K, Sharif M. Biomarkers for diagnosis of osteoartritis. JSM Bone Joint Dis. 2017;1(1):1002.Google Scholar
  5. 5.
    Hussain SM, Neilly DW, Baliga S, Patil S, Meek R. Knee osteoarthritis: a review of management options. Scott Med J. 2016;61(1):7–16. Scholar
  6. 6.
    Sinusas K. Osteoarthritis: diagnosis and treatment. Am Fam Physician. 2012;85(1):49–56.PubMedGoogle Scholar
  7. 7.
    Braun HJ, Gold GE. Diagnosis of osteoarthritis: imaging. Bone. 2011;51(2):278–88.CrossRefGoogle Scholar
  8. 8.
    Abhishek A, Doherty M. Diagnosis and clinical presentation of osteoarthritis. Rheum Dis Clin N Am. 2013;39(1):45–66. Scholar
  9. 9.
    Swagerty DL, Hellinger D. Radiographic assessment of osteoarthritis. Am Fam Physician. 2001;64(2):279–87.PubMedGoogle Scholar
  10. 10.
    Culvenor AG, Øiestad BE, Hart HF, Stefanik JJ, Guermazi A, Crossley KM. Prevalence of knee osteoarthritis features on magnetic resonance imaging in asymptomatic uninjured adults: a systematic review and meta-analysis. Br J Sports Med. Published Online First: 09 June 2018.
  11. 11.
    Yucesoy B, Charles LE, Baker B, Burchfiel CM. Occupational and genetic risk factors for osteoarthritis: a review. Work. 2015;50(2):261–73.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Glyn-Jones S, Palmser AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87. Scholar
  13. 13.
    Murray CJ, Lopez AD. Evidence-based health policy—lessons from the global burden of disease study. Science. 1996;274(5288):740–3.CrossRefGoogle Scholar
  14. 14.
    Kulkarni K, Karssiens T, Kumar V, Pandit H. Obesity and osteoarthritis. Maturitas. 2016;89:22–8. Scholar
  15. 15.
    Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum. 2009;60(12):3546–53.CrossRefGoogle Scholar
  16. 16.
    Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072.CrossRefGoogle Scholar
  17. 17.
    Wan R, Hu J, Zhou Q, Wang J, Liu P, Wei Y. Application of co-expressed genes to articular cartilage: new hope for the treatment of osteoarthritis (review). Mol Med Rep. 2012;6(1):16–8. Scholar
  18. 18.
    Luan Y, Kong L, Howell DR, Ilalov K, Fajardo M, Bai XH, et al. Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-microglobulin. Osteoarthr Cartil. 2008;16(11):1413–20.CrossRefGoogle Scholar
  19. 19.
    Cuellar JM, Cuellar VG, Scuderi GJ. α2-microglobulin autologous protease inhibition technology. Phys Med Rehabil Clin N Am. 2016;27:909–18.CrossRefGoogle Scholar
  20. 20.
    Scuderi GJ, Golish SR, Cook FF, Cuellar JM, Bowser RP, Hanna LS. Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury. J Bone Joint Surg Am. 2011 Feb 16;93(4):336–40. Scholar
  21. 21.
    Larsson S, Lohmander LS, Struglics A. Synovial fluid level of aggrecan ARGS fragments is a more sensitive marker of joint disease than glycosaminoglycan or aggrecan levels: a cross-sectional study. Arthritis Res Ther. 2009;11(3):R92.CrossRefGoogle Scholar
  22. 22.
    Maniar KH, Jones IA, Gopalakrishna R, Vangsness CT Jr. Lowering side effects of NSAID usage in osteoarthritis: recent attempts at minimizing dosage. Expert Opin Pharmacother. 2018;19(2):93–102. Scholar
  23. 23.
    Law TY, Nguyen C, Frank RM, Rosas S, McCormick F. Current concepts on the use of corticosteroid injections for knee osteoarthritis. Phys Sportsmed. 2015;43(3):269–73. Scholar
  24. 24.
    Gregori D, Giacovelli G, Minto C, Barbetta B, Gualtieri F, Azzolina D, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320(24):2564–79. Scholar
  25. 25.
    Bliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons - a scoping review. Obes Rev. 2014;15(7):578–86.CrossRefGoogle Scholar
  26. 26.
    Rizzo J. Patients’ mental models and adherence to outpatient physical therapy home exercise programs. Physiother Theory Pract. 2015;31(4):253–9. Scholar
  27. 27.
    Hackinger S, Trajanoska K, Styrkarsdottir U, Zengini E, Steinberg J, Ritchie G, et al. Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus. Hum Mol Genet. 2017;26(19):3850–8.CrossRefGoogle Scholar
  28. 28.
    Evidence Development and Standards Branch. Health Quality Ontario. Arthroscopic debridement of the knee: an evidence update. Ont Health Technol Assess Ser. 2014;14(13):1–43 Published 2014 Nov 1.Google Scholar
  29. 29.
    van der Woude J, Wiegant K, van Heerwaarden RJ, Spruijt S, van Roermund PM, Custers R, et al. Knee joint distraction compared with high tibial osteotomy: a randomized controlled trial. Knee Surg Sports Traumatol Arthrosc. 2016;25(3):876–86.CrossRefGoogle Scholar
  30. 30.
    Intema F, Van Roermund PM, Marijnissen AC, Cotofana S, Eckstein F, Castelein RM, et al. Tissue structure modification in knee osteoarthritis by use of joint distraction: an open 1-year pilot study. Ann Rheum Dis. 2011;70(8):1441–6.CrossRefGoogle Scholar
  31. 31.
    Wang S, Wei X, Zhou J, Zhang J, Li K, Chen Q, et al. Identification of alpha 2 microglobulin (A2M) as a master inhibitor of cartilage degrading factors that attenuates post-traumatic osteoarthritis progression. Arthritis Rheum. 2014;66(7):1843–53. Scholar
  32. 32.
    Doan N, Gettins PG. Human alpha2-macroglobulin is composed of multiple domains, as predicted by homology with complement component C3. Biochem J. 2007;407(1):23–30.CrossRefGoogle Scholar
  33. 33.
    Sottrup-Jensen L, Stepanik TM, Kristensen T, Wjerzbicki DM, Jones CM, Lenblad PB, et al. Primary structure of human alpha 2-macroglobulin. V. The complete structure. J Biol Chem. 1984;259(13):8318–27.PubMedGoogle Scholar
  34. 34.
    Zhang Y, Wei X, Browning S, Scuderi G, Hanna LS, Wei L. Targeted designed variants of alpha-2-macroglobulin (A2M) attenuate cartilage degeneration in a rat model of osteoarthritis induced by anterior cruciate ligament transection. Arthritis Res Ther. 2017;19(175).
  35. 35.
    Wang S, Wei X, Zhou J, Zhang J, Li K, Chen Q, Terek R, Fleming BC, Goldring MB, Ehrlich MG, Zhang G, … Wei L Identification of Α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(1843)1853. Scholar
  36. 36.
    Cuellar JM, Browning SR, Cuellar VG, Golish SR, Hanna L, Scuderi G. Poster 10 is there a chondroprotective effect of autologous platelet integrated concentrate (APIC) on an osteoarthritis (OA) rabbit model? A pilot study. Pm&R. 2012. Scholar
  37. 37.
    Tortorella MD, Arner EC, Hills R, Easton A, Korte-Sarfaty J, Fok K, et al. Α2-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. Scholar
  38. 38.
    Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med. 2017;45:339–46. Scholar
  39. 39.
    Paterson KL, Nicholls M, Bennell KL, Bates D. Intra-articular injection of photo-activated platelet-rich plasma in patients with knee osteoarthritis: a double-blind, randomized controlled pilot study. BMC Musculoskelet Disord. 2016;17:67. Scholar
  40. 40.
    Duif C, Vogel T, Topcuoglu F, Spyrou G, von Schulze Pellengahr C, Lahner M. Does intraoperative application of leukocyte-poor platelet-rich plasma during arthroscopy for knee degeneration affect postoperative pain, function and quality of life? A 12-month randomized controlled double-blind trial. Arch Orthop Trauma Surg. 2015;135:971–7. Scholar
  41. 41.
    Spaková T, Rosocha J, Lacko M, Harvanová D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil. 2012;91:411–7. Scholar
  42. 42.
    Kon E, Buda R, Filardo G, Di Martino A, Timoncini A, Cenacchi A, et al. Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:1490–501. Scholar
  43. 43.
    Charousset C, Zaoui A, Bellaiche L, Bouyer B. Are multiple platelet-rich plasma injections useful for treatment of chronic patellar tendinopathy in athletes?: a prospective study. Am J Sports Med. 2014;42:906–11. Scholar
  44. 44.
    Li M, Zhang C, Ai Z, Yuan T, Feng Y, Jia W. Therapeutic effectiveness of intra-knee-articular injection of platelet-rich plasma on knee articular cartilage degeneration. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2011.Google Scholar
  45. 45.
    Chen SH, Kuan TS, Kao MJ, Wu WT, Chou LW. Clinical effectiveness in severe knee osteoarthritis after intra-articular platelet-rich plasma therapy in association with hyaluronic acid injection: three case reports. Clin Interv Aging. 2016;Volume 11:1213–9. Scholar
  46. 46.
    Gobbi A, Karnatzikos G, Mahajan V, Malchira S. Platelet-rich plasma treatment in symptomatic patients with knee osteoarthritis: preliminary results in a group of active patients. Sports Health. 2012;4:162–72. Scholar
  47. 47.
    Gibbs N, Diamond R, Sekyere EO, Thomas WD. Management of knee osteoarthritis by combined stromal vascular fraction cell therapy, platelet-rich plasma, and musculoskeletal exercises: a case series. J Pain Res. 2015.
  48. 48.
    Bowman KF, Muller B, Middleton K, Fink C, Harner CD, Fu FH. Progression of patellar tendinitis following treatment with platelet-rich plasma: case reports. Knee Surg Sports Traumatol Arthrosc. 2013;21:2035–9. Scholar
  49. 49. New York (NY): New York University School of Medicine 2017 Nov 1–2019 Mar 12. Identifier NCT03656575, Reduction of pro-inflammatory synovial fluid biomarkers in osteoarthritis of the knee with alpha-2 macroglobulin;
  50. 50.
    Scuderi GJ. Palo Alto (CA): Stanford University Hospital 2017 Oct 9. Identifier NCT01613833, Serum and synovium protease inhibitor levels in primary and secondary osteoarthritic joints;

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vwaire Orhurhu
    • 1
    Email author
  • Ruben Schwartz
    • 2
  • Jacob Potts
    • 3
  • Jacqueline Peck
    • 2
  • Ivan Urits
    • 1
  • Mariam Salisu Orhurhu
    • 4
  • Charles Odonkor
    • 5
  • Omar Viswanath
    • 6
    • 7
    • 8
  • Alan Kaye
    • 9
  • Jatinder Gill
    • 1
  1. 1.Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA
  2. 2.Department of AnesthesiologyMount Sinai Medical Center of FloridaMiamiUSA
  3. 3.Department of BioengineeringNortheastern UniversityBostonUSA
  4. 4.Departments of Anesthesiology and Critical Care MedicineJohns Hopkins School of MedicineBaltimoreUSA
  5. 5.Department of Anesthesia, Critical Care and Pain Medicine, Division of Pain, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  6. 6.Valley Anesthesiology and Pain ConsultantsPhoenixUSA
  7. 7.Department of AnesthesiologyUniversity of Arizona College of Medicine-PhoenixPhoenixUSA
  8. 8.Department of AnesthesiologyCreighton University School of MedicineOmahaUSA
  9. 9.Department of AnesthesiologyLouisiana State University Health Sciences CenterNew OrleansUSA

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