The anti-inflammatory and immunosuppressive effects of corticosteroids are well known. Corticosteroids act directly on nuclear steroid receptors and interrupt the inflammatory and immune cascade at different stages. They reduce vascular permeability and inhibit accumulation of inflammatory cells, phagocytosis, production of neutrophil superoxide, matrix metalloprotease (MMP), and metalloprotease activator, and prevent the synthesis and secretion of several inflammatory mediators such as prostaglandin and leukotrienes [8].

Clinically, corticosteroids reduce the erythema, swelling, heat and tenderness of inflamed joints, as well as stimulate an increase in the relative viscosity of synovial fluid due to a higher hyaluronic acid concentration [9].

The mechanism of action of HA has six main effects: analgesia, an anti-inflammatory effect, a chondroprotective effect, encouraging of proteoglycan and glycosaminoglycan synthesis, improving subchondral bone compliancy and mechanical improvement.

HA does not directly bind to bradykinin receptors, but provides analgesic effects through interaction with HA receptors and free nerve endings within the joint tissue. This analgesic effect occurs at mechanosensitive stretch-activated ion channels, where channel activity is significantly decreased when HA binds, reducing the action of joint nociceptors. Sensitized nociceptive terminals within the joint tissue are affected by HA concentration, reducing the pain response exhibited by these terminals. HMW HA decreases the mechanical sensitivity of stretch-activated ion channels, blocking the pain response. Low molecular weight (LMW) HA seems to be less effective in blocking this response [10].

The anti-inflammatory effect is based on suppression of interleukin (IL) – 1 beta (IL-1β) expression, which is a key mediator of inflammation which is regulated through the binding of HA to CD44 (a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration). IL-1β suppression results in a down-regulation of MMPs, which also aids in the anti-inflammatory effect of HA. Further suppression of pro-inflammatory mediators IL-8, IL-6, PGE2 (prostaglandin E2) and tumor necrosis factor (TNFα) provides the anti-inflammatory effects of intra-articular HA. Degradation products of HA produce an inflammatory response mediated via interaction between CD44 and Toll-like Receptors (TLR). This pro-inflammatory response results in increased nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-кB), IL-1β, TNFα, IL-6 and IL-33 production. HMW HA has been demonstrated to suppress numerous inflammatory mediators through TLR 2 (toll-like receptor 2) and 4 binding, including TNF-α, IL-1-β, IL-17, MMP-13 and inducible nitrogen oxide synthase (iNOS). A direct correlation between molecular weight and anti-inflammatory effects has demonstrated longer effects of PGE2 and IL-6 inhibition for HMW HA treatment. IL-6 is a pro-inflammatory cytokine, regulated by Nf-кB. HA binding to ICAM-1 (intercellular adhesion molecule-1) down-regulates Nf-кB, which in turn decreases the production of IL-6. Down regulation of TNFα, IL-1B and IL-8 is an additional contributory factor to the anti-inflammatory effects provided by HMW HA [11].

Intra-articular HA has direct chondroprotective effects. HA is thought to reduce chondrocyte apoptosis, while increasing chondrocyte proliferation. The binding of HA to CD44 inhibits interleukin (IL)-1β expression, leading to a reduction in matrix metalloproteinase (MMP) production [12]. This binding to CD44 has been shown to be of greater effect for HMW HA products. HA also binds to the receptor for hyaluronan mediated motility (RHAMM), which is thought to aid in chondroprotection in addition to the CD44-mediated effect. The inhibition of IL-1β expression through CD44 binding is carried out through induction of mitogen-activated protein kinase phosphatase (MKP) -1: a negative regulator of IL-1β [13].

Chondrocyte apoptotic events are further decreased by the binding of HA to CD44 through the reduction of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) expression. These peptidases are involved in the cleavage of important synovial components, including aggrecan, versican and brevican. ADAMTS expression has been shown to be reduced as a result of HA-CD44 binding, providing an additional mode of chondroprotection for HA treatment [14]. The production of reactive oxygen species (ROS), such as nitric oxide (NO), results in degeneration of cartilage through increased chondrocyte apoptosis. IA HA treatment leads to a reduction in IL-1β-induced oxidative stress, through inhibition of NO production within the synovium. Additional results of CD44-HA binding resulting in chondroprotective effects include reduction of prostaglandin E2 (PGE2) synthesis, and increase of heat shock protein 70 (Hsp70) expression. These effects provide therapeutic benefit through the reduction of chondrocyte apoptosis [15]. HMW HA products demonstrate more inhibition of PGE2 expression than LMW, resulting in a greater chondroprotective effect.