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With HA, Size Matters

Normal, healthy synovial fluid contains hyaluronan (HA) with a molecular weight of 2-3 million daltons (MDa). This polymer of d-glucuronic acid and n-acetyl-d-glucosamine can be thousands of disaccharide units in length.

This very large compound traps up to 1,000 times its own weight in water1 contributing to the cushioning and lubricating properties of synovial HA with the larger sized molecules associated with different physiologic effects than smaller HA molecules.2,3 This is important since both the concentration and the molecular weight of HA decreases in inflamed joints.4,5
Smaller molecular weight HA is not the same as the normal size molecule.3 As the molecular weight decreases, fluid viscosity decreases.6 Based on studies of intra-articular injections of HA in humans and rats, the higher molecular weight HA molecules can relieve pain.7,8,9 Larger molecules are associated with greater and longer-lasting pain reduction in rats.10
This suggests that the reduced HA concentration and molecular weight contributes to or fails to ameliorate joint pain. The smaller HA molecules are less beneficial to cartilage elasticity, as well.11 This may explain subsequent cartilage damage in inflamed joints.

Hundreds of studies have examined the physiologic roles of HA and found HA involved in anti-inflammation, anti-oxidation, immune cell activation in addition to joint lubrication, cartilage support and pain control.3 Molecular weight affects HA biological activity in all of these roles. The anti-inflammatory character changes to one that is pro-inflammatory as size decreases.12 Smaller sized molecules participate in the activation of eosinophils.13 Larger molecules suppress cytokine production in mice.14,15

Hyaluronan physiologic function varies with molecular weight. Intra-articular injection of 1.5 MDa in canine joints that normally contain 2-3 MDa HA failed to provide benefit.4 This is consistent with studies in rabbits showing that the benefit is less when HA replacement is done with a molecular weight below that of the native HA.16

Similar studies in humans with existing products for intra-articular injection found differing efficacies on a variety of parameters; molecular weight varied among the products.17 Not all HA is the same.17,18

Summary
High molecular weight HA is associated with the beneficial roles that we expect in a healthy joint, so it is important to support the synovial HA in a stressed joint with a molecular weight that matches native HA: 2 to 3 MDa.
When it comes to HA - Bigger IS better!

References
1. Laurent, T., & Fraser, J. (1992). Hyaluronan. Faseb J, 6 (7), 2397-2404.
2. Carmenisch, T., & MacDonald, J. (2000). Hyaluronan: is bigger better? Am J Respir Cell Mol Biol , 23 (4), 431-433.
3. Bucci, L., & Turpin, A. (2004). Will the real hyaluronan please stand up? J of Appl Nutr , 54 (1), 10-33.
4. Smith, G., Mickler, E., Myers, S., & Brandt, K. (2001). Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine post-traumatic osteoarthritis. J Rheumatol , 28 (6), 1341-1346.
5. Budsberg, S., Lenz, M., & Thonar, E. (2006). Serum and synovial fluid concentrations of keratan sulfate and hyaluronan in dogs with induced stifle joint osteoarthritis following cranial cruciate ligament transection. Am J Vet Res , 67 (3), 429-432.
6. Kuo, J.-W. (2005). Practical Aspects of Hyaluronan-based Medical Products. CRC Press.
7. Moreland, L. (2003). Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther , 5 (2), 54-67.
8. Yeung, R., Chow, R., N, S., & Chiu, K. (2006). Short-term therapeutic outcome of intra-articular high molecular weight hyaluronic acid injection for non-reducing disc displacement of the temporomandibular joint. Oral Surg Oral Med Oral Pathol Oral Radiol Endod , 102 (4), 453-461
9. Waddell, D. (2007). Viscosupplementation with hyaluronans for osteoarthritis of the knee: clinical efficacy and economic implications. Drugs Aging , 24 (8), 629-642.
10. Gotoh, S., Onaya, J., Abe, M., Miyazaki, K., Hamai, A., Horie, K., et al. (1993). Effects of the molecular weight of hyaluronic acid and its action mechanisms on experimental joint pain in rats. Ann Rheum Dis , 52 (11), 817-822.