BackgroundKnee osteoarthritis (OA) is one of the leading causes of disability within the adult population. Current treatment options for OA of the knee include intra-articular (IA) hyaluronic acid (HA), a molecule found intrinsically within the knee joint that provides viscoelastic properties to the synovial fluid. A variety of mechanisms in which HA is thought to combat knee OA are reported in the current basic literature.MethodsWe conducted a comprehensive literature search to identify currently available primary non-clinical basic science articles focussing on the mechanism of action of IA-HA treatment. Included articles were assessed and categorized based on the mechanism of action described within them. The key findings and conclusions from each included article were obtained and analyzed in aggregate with studies of the same categorical assignment.ResultsChondroprotection was the most frequent mechanism reported within the included articles, followed by proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, mechanical, subchondral, and analgesic actions. HA-cluster of differentiation 44 (CD44) receptor binding was the most frequently reported biological cause of the mechanisms presented. High molecular weight HA was seen to be superior to lower molecular weight HA products. HA derived through a biological fermentation process is also described as having favorable safety outcomes over avian-derived HA products.ConclusionsThe non-clinical basic science literature provides evidence for numerous mechanisms in which HA acts on joint structures and function. These actions provide support for the purported clinical benefit of IA-HA in OA of the knee. Future research should not only focus on the pain relief provided by IA-HA treatment, but the disease modification properties that this treatment modality possesses as well.

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Objective Osteoarthritis (OA) is one of the leading causes of disability in the adult population. Common nonoperative treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and intra-articular injections of hyaluronic acid (HA). HA is found intrinsically within the knee joint providing viscoelastic properties to the synovial fluid. HA therapy provides anti-inflammatory relief through a number of different pathways, including the suppression of pro-inflammatory cytokines and chemokines. Methods We conducted a systematic review to summarize the published literature on the anti-inflammatory properties of hyaluronic acid in osteoarthritis. Included articles were categorized based on the primary anti-inflammatory responses described within them, by the immediate cell surface receptor protein assessed within the article, or based on the primary theme of the article. Key findings aimed to describe the macromolecules and inflammatory-mediated responses associated with the cell transmembrane receptors. Results Forty-eight articles were included in this systematic review that focused on the general anti-inflammatory effects of HA in knee OA, mediated through receptor-binding relationships with cluster determinant 44 (CD44), toll-like receptor 2 (TLR-2) and 4 (TLR-4), intercellular adhesion molecule-1 (ICAM-1), and layilin (LAYN) cell surface receptors. Higher molecular weight HA (HMWHA) promotes anti-inflammatory responses, whereas short HA oligosaccharides produce inflammatory reactions. Conclusions Intra-articular HA is a viable therapeutic option in treating knee OA and suppressing inflammatory responses. HMWHA is effective in suppressing the key macromolecules that elicit the inflammatory response by short HA oligosaccharides.