June 16, 2024
Home » Urolithin A vs. Osteoarthritis

Degenerative diseases, specifically those that affect joints and muscle, produce detrimental effects on movement, agility, strength, and quality of life. Numerous nutritional and strength exercise therapies focus on the regeneration of these tissues, mostly slowing the disease progression by modulating inflammatory response. Nowadays, osteoarthritis (OA) affects tens of millions worldwide and associates with joint degradation, loss of articular cartilage, and synovial inflammation. Indeed, OA is a multifactorial condition coinciding with aging, obesity, injury, and joint malformation. Urolithin A, a microbiome-derived metabolite, is associated with powerful anti-inflammatory effects and anti-aging benefits. Let’s find out what the studies say about reversing and preventing OA with UA supplementation. 

OA physiopathology:

Inflammation plays a central part in OA physiopathology. Indeed, studies suggest that elevated levels of pro-inflammatory mediators IL-1b, IL-6, and tumor necrosis factor-alpha (TNF-a) are found in OA cartilage. In addition, extensive research proves that IL-1b is a potent inflammatory response initiator and acts as a master regulator of the inflammatory cascade. 

Furthermore, an IL-1b upregulation stimulated the production of metalloproteinases (MMPs) by chondrocytes. In this pro-inflammatory environment, the combination of MMPs and thrombospondin type 1 motifs (ADAMTS), along with the presence of cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS). Combining these factors results in cartilage alteration, promotes tissue catabolism, and promotes extracellular matrix (ECM) degradation.

UA vs. inflamm-aging

Low-grade inflammation is the continuous exposure of chronic inflammation. This factor is consistent with chronic degenerative diseases and age-related cellular decline resulting in organ and tissue dysfunction.

Several studies using animal models report consistent inflammatory modulatory effects of UA and its metabolic responses. Firstly, UA supplementation can reduce the expression of mRNA and circulatory levels of pro-inflammatory marker cyclooxygenase- 2 in rat models with acute colitis. Following studies in rat models associated UA with reduced inflammatory response inducer IL-1b, resulting in decreased concentration of IL-6 and TNF-A. On the contrary, an elevation of the anti-inflammatory cytokine IL-10 was observed in UA- treated diabetic mice.  

UA mechanism of action in joint disorders 

Between the anti-inflammatory mechanisms mediated by UA, the inhibition of TNF-a at a nuclear level of pulpous cells and the reduction of intervertebral disc degradation have been demonstrated in vivo.

A recent study performed in human chondrocytes intervened with UA demonstrated the anti-inflammatory orchestra of this microbiome-derived metabolite. Some of the mechanisms of action were:

  • UA reduced the levels of MMP3 and MMP13 in previously IL-1b-treated chondrocytes. This effect was associated with an attenuation of the expression of iNOS and COX-2.
  • The decrease of MMP3 resulted in an increase in Collagen II and proteoglycan synthesis.
  • Another crucial benefit associated with UA was the upregulation of Sox-9. Furthermore, Sox-9 is a transcription factor that modulated Collagen II synthesis, the cornerstone of chondrocyte differentiation.
  • In conclusion, this study reported that UA could be used as a therapeutic agent due to its capacity to restore the balance between the cartilage matrix anabolism and catabolism.

 UA modulates MAPK and NF-kb pathways.

Mitogen-activated protein kinase (MAPK) and NF-kb pathways function as master regulators in the process of OA pathology. In a healthy environment, MAPK transmits cellular stimulation signals that induce cell proliferation, differentiation, transformation, and apoptosis. However, in a pro-inflammatory environment, three key members of this pathway can act as potent initiators of a pro-inflammatory cascade. Indeed, elevated concentrations of the extracellular regulated kinase (ERK), N-terminal kinase (JNK), and p38 are found in synovial tissue and cartilage lesion. This upregulation reflects in articular damage caused by a higher concentration of MMPs-induced by activating these three factors and IL-1b inflammatory milieu.

Furthermore, IL-1b can stimulate NF-kB activation and nuclear translocation, resulting in an elevated expression of iNOS and COX-2. Consequently, this cascade reaction catalyzes the NO, increasing MMPs, which attenuates collagen II and proteoglycan synthesis. 

Concurrently, the study performed by Shen-long et al. reported that UA intervention could potentially reduce lipopolysaccharide-induced inflammation. Ultimately, this mechanism would decrease the MAPK and NF-kB pathways and promote an anabolic environment in the joint tissues. However, the same authors report that more information is still to be elucidated on this topic, and further research is needed. 

The inflammatory mechanism that promotes osteoarthritis can be prevented, reversed, and treated. Although, we have to consider that inflammation can be enabled by excessive fat mass, elevated concentration on ROS, and dietary components. Therefore, treating this age-related condition can be supported by weight reduction therapy, proper physical exercise, and nutritional advice. Furthermore, nutritional treatment should include an anti-inflammatory diet that enables a beneficial microbiome that can promote the formation of UA.- Ana Paola Rodríguez Arciniega, MS.


Ding, Sheng-Long et al. “Urolithin a attenuates IL-1β-induced inflammatory responses and cartilage degradation via inhibiting the MAPK/NF-κB signaling pathways in rat articular chondrocytes.” Journal of inflammation (London, England) vol. 17 13. 24 Mar. 2020, doi:10.1186/s12950-020-00242-8

D’Amico, Davide et al. “Impact of the Natural Compound Urolithin A on Health, Disease, and Aging.” Trends in molecular medicine vol. 27,7 (2021): 687-699. doi:10.1016/j.molmed.2021.04.009

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