Osteoarthritis (OA) is a multifactorial degenerative muscle-skeletal disease with no curative treatment. OA is characterized by a low-grade inflammation and deep morphological changes in cartilage as well as in subchondral bone. Cartilage fragmentation is the cause of synovial inflammation that is now recognised as a key process of OA joint pathology. OA aetiology is not fully understood. However, it has been suggested that chondrocytes inflammatory responses could mediate OA in terms of development and progression. One of the factors involved in these responses is IL-1, a cytokine proposed as a driver of OA disease. Nevertheless, therapeutics attempts driven to target IL-1 are not able to control OA symptoms.
In light of this, there is a growing interest in studying other potential targets, in order to develop new therapeutic approaches to halt OA progression. Recently, Toll-like receptors (TLRs) are emerging as potential new targets for OA. High levels of TLRs agonists are present in OA joints and TLRs have been associated with OA. Particularly, it has been reported that TLR4 is associated with OA mediating cytokines production and inflammatory responses in chondrocytes. TLR4 binds a number of different agonists, for example, the pathogen-associated molecular patterns (PAMPs), such as LPS, but also recognize damage-associated molecular patterns (DAMPs), some of which are released when tissues are damaged.
Several molecules involved in TLR4 activation have an important role in cartilage inflammatory responses and in the development and progression of cartilage degradation. There is increasing evidence that nitric oxide (NO) is one of the factors induced by TLR4 activation and its excessive production is associated with OA progression. NO is a short-lived gaseous mediator of inflammatory response mainly produced by nitric oxide synthase (NOS2) and highly produced by chondrocytes upon pro-inflammatory cytokine stimulation. This pleiotropic free radical regulates the synthesis of several catabolic enzymes like matrix metalloproteinases (MMPs), which play a key role in the OA-associated cartilage degradation through the induction of the breakdown of cartilage matrix components.
Several cytokines and chemokines are also associated with TLR4 activation and are involved in cartilage inflammatory responses leading to the development and progression of cartilage degradation. For instance, TNF-α, IL-6 and IL-8 have been implicated in OA progression as well as chemokine MIP-1α.
Current treatment options to manage OA are not curative and fail to reverse the degenerative process of OA. Thus, the need for effective OA treatment, with lower side effects than those exerted by NSAIDs or analgesic drugs such as acetaminophen, is of particular relevance.
Vegetal–derived compounds show relevant pharmacological properties that can be explored in the context of cartilage pathophysiology to identify novel molecules as well novel pharmacological properties of natural compounds. Oleocanthal (OC) is a phenolic component of extra virgin olive oil (EVOO), the main lipid component of the Mediterranean diet. OC (oleo-for olive, canth-for sting, and –al for aldehyde) is responsible for the throat burn characteristic of many EVOOs.
OC was described to inhibit COXs in cell-free enzymatic assay in a way similar to well-known no steroidal anti-inflammatory drug (NSAID) used in the standard pharmacological intervention of OA.
Several studies evidenced novel relevant pharmacological properties of OC in different pathogenic processes. Our group elucidated the anti-inflammatory properties of oleocanthal in LPS-activated murine macrophages J774 and ATDC5 murine chondrogenic cells. In addition, we demonstrated a potent in vitro anti proliferative mechanism exerted by oleocanthal in human and mouse multiple myeloma cells. This anti-cancer activity of OC was confirmed by several other studies. OC is also associated with a reduced risk of neurodegenerative diseases, such as Alzheimer’s disease. However, nothing is known about the effect of OC in human OA pathology.
Therefore, the current study aimed at identifying the effect of OC in LPS-stimulated human primary chondrocytes from OA patients. Moreover, we investigate the signalling pathway involved in this process, focusing on the activation of ERK 1/2, P38 and the IkB/ NF-kB pathway.