Mechanisms of Action of Intra-articular Hyaluronic Acid Injections for Knee Osteoarthritis: A Targeted Review of the Literature.

Abstract

Background: The knee is the most commonly afflicted joint in osteoarthritis (OA). Injection of intra-articular of hyaluronic acid (IAHA) is a frequently used therapy for the management of knee OA with varying product characteristics.

Purpose: To describe and characterize the mechanism of action (MoA) of IAHA products concerning nociception, chondroprotection, and anti-inflammatory properties via a targeted literature review.

Study design: Systematic review; Level of evidence, 2.

Methods: We followed the standard methodologies for conducting and reporting targeted reviews as recommended by the Cochrane Handbook for Systematic Reviews of Interventions, adapted for conducting a targeted literature review. Relevant studies were identified by searching the Embase database using predefined search strategies via the Ovid platform. The results of the review were reported according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses).

Results: A total of 182 studies were included in this targeted literature review. Of these, 107 reported chondroprotective action, 59 anti-inflammatory activity, 18 analgesic properties, 30 proteoglycan or glycosaminoglycan synthesis, 8 subchondral bone effects, 2 mechanical effects, and 1 other effects of IAHA. These MoAs were studied through diverse types of studies: in vitro biochemistry, animal physiological studies, or human physiological and clinical studies. The chondroprotective effect was the most studied MoA and showed an increase in anabolic biomarkers, such as collagen types II, IX, and XI, and a reduction in catabolic biomarkers, such as matrix metalloproteinases, which play a primary role in the downstream signaling pathways in OA and cartilage degradation in the synovial fluid. IAHA was widely reported by studies to reduce soluble inflammatory mediators, such as interleukins 1β and 6 and tumor necrosis factor α, thereby decreasing the production of degradative enzymes (eg, matrix metalloproteinases, aggrecanases). IAHA was also reported to enhance the synthesis of intrinsic proteoglycan (eg, aggrecan) and glycosaminoglycans, thus delaying the progression of OA. IAHA also reported improvement in the mechanical function of the knee by increasing the viscosity of the synovial fluid, reducing the coefficient of friction, and improving its lubrication. Overall, a significant decrease in knee pain was observed after IAHA treatments.

Conclusion: Preclinical and clinical studies established evidence for varied MoAs by which IAHA preparations may produce a desired effect in patients with knee OA.