Synergy between cyclooxygenase-2 inhibitors and hyaluronic acid in the treatment of osteoarthritis: Illumination of signaling cascade, nanotechnology-driven delivery strategies and future prospects

Osteoarthritis (OA) is generally caused by a variety of risk factors, the most notable of which are growing age and obesity. Pathophysiologically, chondrocytes alter their morphology and communicate a set of signalling cascades in response to numerous stimuli such as cytokines, chemokines, alarmins, damage-associated molecular patterns, and adipokines. Pharmacological therapies are primarily concerned with symptom alleviation, and no illnessaltering OA medication has yet been licensed by regulatory bodies. Hyaluronic acid (HA) is a naturally occurring non-sulphated non-protein glycosaminoglycan entity with distinct physicochemical properties. Interestingly, HA in combination with cyclooxygenase-2 (COX-2) inhibitors has sparked immense attraction due to its viscosupplementation, chondroprotective and anti-inflammatory chattels. The cross-talk of HA with COX-2 inhibitors suppresses the formation of nitric oxide to prevent chondrocyte apoptosis via acting on the MAPK (Mitogenactivated protein kinases) pathway. HA suppresses p38 MAPK activation in profoundly deteriorated chondrocytes and inhibits the translocation and transcription factors. This sequence ultimately impedes the release of pro-inflammatory cytokines and decreases expression of COX-2 enzyme. On the other hand, the viscoelastic property of high molecular weight HA may be attributed to inter-and intra-chain interaction and formation of crosslinks at higher concentrations. Therefore, in the present review, an attempt has been undertaken to unbox the interactions between COX-2 inhibitors and HA. We have also highlighted the key role and merits of COX-2 inhibitors and HA used either alone or in combination, as a vital therapy for OA patients using in-silico docking tools. A plethora of nanotechnology-driven strategies employed to deliver COX-2 inhibitors and HA in the management of OA is also summarized.