How the Olive-Based Antioxidant Oleuropein Supports Healthy Joints

Chronically inflamed knee joints are a leading cause of disability among older adults, causing severe debilitation and loss of mobility. As most researchers believe it to be incurable, current treatments involve managing symptoms of immobility and inflammation. However, a recent study authored by the CellCOM Research Group in Spain suggests that a new regenerative therapy for inflamed knee joints using a compound found in olives may soon provide relief to the 30 million Americans suffering from this degenerative condition. 

Wearing-and-tearing down cartilage

Inflamed knee joints are often referred to as “wear-and-tear," as this condition tends to occur after injury or with increasing age. It develops when the protective cartilage between bones breaks down, causing the otherwise-cushioned joints to grind together. This leads to inflamed and swollen joints, most commonly occurring in the hands, knees, neck, hips, and lower back. 

Specifically, inflamed knee joints develop when articular cartilage — the smooth, white tissue that covers the ends of bones where they come together to form joints — degenerates. This protective tissue is made up of a three-dimensional network of compounds called the extracellular matrix (ECM). This structural support system primarily consists of collagen, proteins called proteoglycans, water, and chondrocytes, which are specialized and metabolically active cartilage tissue cells. 

Conditions of inflamed knee joints develop due to a multitude of reasons, including a degradation of the ECM structure, a decrease in the metabolic activity and reparative ability of chondrocytes, and a buildup of inflammatory senescent cells, which have permanently stopped dividing and lost function. Researchers believe that many of these processes are mediated by a protein called connexin-43 (Cx43) that is involved with communication between the gap junctions of cells. 

Connexin-g the gaps: too much of a good thing 

Gap junctions are small channels that allow for chemical and molecular signals to pass between neighboring cells, a process referred to as gap junction intercellular communication (GJIC). One of the primary proteins involved in GJIC is Cx43, a gap junction protein. 

Although the connexin family and GJIC are both vital to overall cellular health and homeostasis, overexpression of Cx43 leads to excessive between-cell signaling. This increase in communication alters the balance between cellular processes called redifferentiation and dedifferentiation. 

Briefly, differentiation is the process of immature stem cells developing into specialized cells. In the context of bone health, mesenchymal stem cells differentiate into the bone-forming osteoblasts. Dedifferentiation occurs when these specialized cells revert into a stem-like state but are unable to divide. Conversely, redifferentiation is when these dedifferentiated cells regain their ability to divide and can once again develop into specialized cells. In joint-related disorders, redifferentiation is an essential process that attempts to reverse tissue loss after injury.

Essentially, too much Cx43 leads to the dedifferentiation of osteoblasts and chondrocytes due to excessive GJIC.. An accumulation of dedifferentiated chondrocytes stuck in this stem-like state can impair tissue regeneration and lead to conditions of inflamed knee joints.

Another factor that plays a role in conditions of inflamed knee joints is a buildup of senescent cells. Rather than being eliminated, senescent cells remain in the body and damage nearby tissues and cells by secreting inflammatory compounds that can lead to inflamed knee joints. 

Recent research, also from the CellCOM Research group, found that reducing Cx43 levels in chondrocyte cells decreased both senescent cells and stem-like cells, indicating that lowering Cx43 could be a therapeutic target for conditions of inflamed knee joints. As high levels of Cx43 are consistently found in inflamed cartilage tissue, this seems like a good place to start. 

The use of senolytics — compounds that clear out senescent cells — has been shown to reduce the cartilage and joint degeneration that is indicative of conditions of inflamed knee joints. With this knowledge, the CellCOM team aimed to uncover compounds that could mitigate both senescence and high Cx43 levels — and they may have found it with a compound naturally occurring in olives. 

Overhauling inflamed knee joints with oleuropein 

Oleuropein is an anti-inflammatory compound with antioxidant properties found in the fruit and leaves of the olive plant. The major metabolite of oleuropein is hydroxytyrosol, which also acts as an antioxidant and reduces the activation of pro-inflammatory signaling pathways that are involved in conditions of inflamed knee joints.  

Previous research has linked olives, olive oil, or oleuropein to improvements in conditions of inflamed knee joints, but how this happens was unknown. In this study, researchers assessed the impact of oleuropein on three components of conditions of inflamed knee joints: Cx43 levels, chondrocyte senescence, and overall cartilage degradation. To do this, the team treated chondrocyte cell cultures with induced conditions of inflamed knee joints and human mesenchymal stem cells (hMSCs) with oleuropein and olive extract. 

After oleuropein and olive extract treatment, both of the cell types studied showed significantly reduced Cx43 levels and GJIC activity. Additionally, the accumulation of senescent cells that are typically seen after injury was mitigated after just 24 hours of treatment. 

Oleuropein also reduced inflammatory markers called cytokines and levels of MMP-13, an enzyme that degrades collagen in the ECM. Lastly, the olive-based compound increased the rates of chondrocyte redifferentiation, the production of ECM proteoglycans, and the activity of Col2A1, a gene related to collagen production. 

Looking forward, from senolytics to stem cell therapy 

Oleuropein’s ability to reduce Cx43 and GJIC levels while slowing cellular senescence may lead to joint regeneration and a slowing of OA progression. These beneficial outcomes indicate that oleuropein could have strong therapeutic potential for patients with OA or other disorders related to joints, cartilage, and bones.

As stem cell injections are currently touted as an OA treatment, the positive results seen with hMSCs in this study suggest that adding oleuropein or olive leaf extract may boost the effectiveness of stem cell therapy. However, as this research involved cell cultures only, it’s too soon to know if the OA-related benefits seen from these olive-based compounds will translate to human studies. 

References:

Chin KY, Pang KL. Therapeutic Effects of Olive and Its Derivatives: From Bench to Bedside. Nutrients. 2017;9(10):1060. Published 2017 Sep 26. doi:10.3390/nu9101060

Feng Z, Li X, Lin J, et al. Oleuropein inhibits the IL-1β-induced expression of inflammatory mediators by suppressing the activation of NF-κB and MAPKs in human chondrocytes. Food Funct. 2017;8(10):3737-3744. doi:10.1039/c7fo00823f

Varela-Eirín M, Carpintero-Fernández P, Sánchez-Temprano A, et al. Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment. Aging (Albany NY). 2020;12(16):15882-15905. doi:10.18632/aging.103801

Varela-Eirín M, Varela-Vázquez A, Guitián-Caamaño A, et al. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment. Cell Death Dis. 2018;9(12):1166. Published 2018 Dec 5. doi:10.1038/s41419-018-1225-2

Yang H, Chen C, Chen H, et al. Navitoclax (ABT263) reduces and promotes chondrogenic phenotype by clearing senescent chondrocytes. Aging (Albany NY). 2020;12(13):12750-12770. doi:10.18632/aging.103177