ENDOTARGET publication: Formononetin, a Beer Polyphenol with Catabolic Effects on Chondrocytes

María Guillán-Fresco, Eloi Franco-Trepat, Ana Alonso-Pérez, Alberto Jorge-Mora, Verónica López-López, Andrés Pazos-Pérez, María Piñeiro-Ramil and Rodolfo Gómez  

2023, Nutrients 

 

Background and Objectives: 

Osteoarthritis (OA) is the most common rheumatic disease and one of the most disabling pathologies worldwide. Diet has been proposed as one of the potentially modifiable risk factors in OA’s development. Specifically, beer consumption has been linked to OA progression. Among the active compounds present in beer, flavonoids stand out. Specifically, formononetin (FNT) is one of the major isoflavonoids present in beer, an estrogenic compound also found in multiple plants and herbs. However, nothing is known about the effects of this isoflavonoid on chondrocyte catabolic and inflammatory responses. In this study, the effect of FNT on chondrocyte viability, inflammation, and metabolism is investigated.

 

Results: 

FNT does not alter chondrocyte viability 

FNT did not alter the metabolic activity and viability of chondrocytes (cartilage cells), even in the presence of IL-1β, a pro-inflammatory cytokine typically associated with OA inflammatory and catabolic environment. 

FNT promotes chondrocyte catabolic responses 

OA is primarily characterised by progressive cartilage degradation, where chondrocyte’s anabolic responses are inhibited, and catabolic ones are promoted. In vitro experiments showed that FNT in chondrocyte cells significantly influenced the expression of relevant genes that play a key role in cartilage maintenance. The obtained expression patterns indicated that FNT promotes a catabolic response in chondrocytes. In the context of OA, this would imply a faster progression of the disease. 

FNT negatively impacts chondrocyte differentiation 

Since FNT is part of different food products and might be exposed to infants through breast milk or infant formulas, the impact of FNT on chondrocyte differentiation was investigated. Chondrocyte differentiation plays a key role in longitudinal bone growth and is also an essential process for bone fracture healing. Therefore, the effect of FNT on expression levels of differentiation and catabolic markers during chondrocyte differentiation was analysed. The results show that FNT in combination with inflammatory stimuli (IL-1β) has a negative impact on chondrocyte differentiation. 

FNT has a predicted strong binding affinity to ERs and AhR 

In silico molecular docking experiments revealed that FNT has a strong binding affinity to estrogenic receptors (ER) and aryl hydrocarbon receptor (AhrR) that is expressed by growth plate chondrocytes that can establish crosstalk with the estrogenic receptors. However, subsequent in vitro experiments have shown that the effect of FNT on chondrocyte differentiation is not mediated by these receptors. 

 

Conclusion:

In conclusion, exposure to FNT at certain concentrations or physiological/pathological status may promote chondrocyte catabolism and thus faster progression of OA. Factors that favor FNT accumulation, such as long times of exposure (e.g., beer consumption throughout life) or metabolic disorders, can promote this catabolic effect, which is independent of both ERs and AhR. These data may provide a partial explanation for why high beer consumption increases the risk of OA. 

Read the full publication: Formononetin, a Beer Polyphenol with Catabolic Effects on Chondrocytes

Glossary:

• Aryl hydrocarbon receptor (AhR): ligand-activated transcription factor particularly pronounced in cells of interfacial organs such as skin, intestine and lung, as well as in most cells of the immune system. It is also expressed by growth plate chondrocytes and can establish crosstalk with ERs.
• Chondrocyte: cartilage cells that synthesise and maintain the cartilaginous matrix in cartilage tissue and are thus crucial for its structure and function. 
• Estrogenic Receptor (ER): plasmatic receptor that is activated by the hormone estrogen and can act as a transcription factor. 
• Formononetin (FNT): one of the major isoflavonoids present in beer with estrogenic properties. 
• Interleukin-1 beta (IL-1β): pro-inflammatory cytokine protein produced by activated immune cells (macrophages) and involved in various cellular activities, including inflammation and immune responses. 
• Osteoarthritis (OA): degenerative joint disease characterised by the breakdown of cartilage, leading to pain, swelling, stiffness, and reduced mobility in affected joints.