Overview of Anti-Inflammatory and Anti-Nociceptive Effects of Polyphenols to Halt Osteoarthritis: From Preclinical Studies to New Clinical Insights

Abstract

Knee osteoarthritis (OA) is one of the most multifactorial joint disorders in adults. It is characterized by degenerative and inflammatory processes that are responsible for joint destruction, pain and stiffness. Despite therapeutic advances, the search for alternative strategies to target inflammation and pain is still very challenging. In this regard, there is a growing body of evidence for the role of several bioactive dietary molecules (BDMs) in targeting inflammation and pain, with promising clinical results. BDMs may be valuable non-pharmaceutical solutions to treat and prevent the evolution of early OA to more severe phenotypes, overcoming the side effects of anti-inflammatory drugs. Among BDMs, polyphenols (PPs) are widely studied due to their abundance in several plants, together with their benefits in halting inflammation and pain. Despite their biological relevance, there are still many questionable aspects (biosafety, bioavailability, etc.) that hinder their clinical application. This review highlights the mechanisms of action and biological targets modulated by PPs, summarizes the data on their anti-inflammatory and anti-nociceptive effects in different preclinical in vitro and in vivo models of OA and underlines the gaps in the knowledge. Furthermore, this work reports the preliminary promising results of clinical studies on OA patients treated with PPs and discusses new perspectives to accelerate the translation of PPs treatment into the clinics.

Keywords: bioactive dietary molecules; inflammation; natural compounds; nutraceuticals; osteoarthritis; pain; polyphenols.

Figure 1

PPs classification. Figure 1 shows the known classes of PPs and the main PPs which constitute each class. The two classes of PPs most represented are flavonoids and phenolic acids. The ‘red concentric symbol’ highlights the most studied PPs in the field of OA inflammation and pain; its size corresponds to the number of studies. Overall, the most studied is resveratrol, followed by epigallocatechin gallate, quercetin, icariin, and hesperetin. To the best of our knowledge the following PPs have never been investigated regarding OA inflammation and pain: syringic acid, cryptochlorogenic acid, neochlorogenic acid, glycitein, dalbergin, neohesperidin, taxifolin, catechin, catechin gallate, gallocatechin, gallocatechin gallate, epicatechin, epigallocatechin, pelargonidin, peonidin, petunidin, dihydrocapsaicin, secoisolariciresinol, matairesinol, lariciresinol, medioresinol, syringaresinol, sesamolin.

Figure 2

Overview and synthesis of the main biological effects of PPs compounds, reported in Table 1 and Table 2, on articular cartilage, synovial membrane and subchondral bone. Red arrows indicate down-regulation. Green arrows report up-regulation.

Figure 3

Schematic representation of main knowledge gaps for the use of PPs for the treatment of OA. The main limitations of their use include mainly the consideration of four aspects: safety, bioavailability, response variability and regulatory aspects. A safety profile should be devoid of cytotoxicity (absence of cell apoptosis, death, etc.), mutagenicity and genotoxicity and immunogenic reactions at a local and systemic level. Bioavailability depends on a certain number of factors, including the route of administration, chemical stability, dose and frequency of BDMs, and gut microbiota (dysbiosis). Response variability of BDMs is closely dependent on the lack of standardization, different formulations batch variations, metabolic state, and microbiota composition which render unreproducible therapeutic effects among OA patients. Finally, the regulatory aspect is another critical limitation due to the lack of universal rules which govern the BDMs process worldwide.

Figure 4

Overview of main perspectives to improve future research approaches studying PPs. The main challenges in this research field are addressed to improve their safety and efficacy profile. We distinguished four main research areas, engineering technology, new formulations, better clinical studies and standardized regulatory rules, which are closely interconnected and require different expertise. Engineering technology can represent a valid tool thanks to the new bio-based delivery systems to preserve PPs efficacy and ensure long-lasting effects in the joint. Better clinical studies should include previous patients’ stratification and more rigorous clinical trials. Combinatorial therapies with cell-based therapies, other BDMs or anti-inflammatory drugs can have synergistic benefits in reducing inflammation and pain. Finally, more standardized regulatory rules among countries could facilitate to reach and speed up of clear-cut conclusions on BDMs.