Inhibitory Effect of Probenecid on Osteoclast Formation via JNK, ROS and COX-2

Abstract

Probenecid is a representative drug used in the treatment of gout. A recent study showed that probenecid effectively inhibits oxidative stress in neural cells. In the present study, we investigated whether probenecid can affect osteoclast formation through the inhibition of reactive oxygen species (ROS) formation in RAW264.7 cells. Lipopolysaccharide (LPS)-induced ROS levels were dose-dependently reduced by probenecid. Fluorescence microscopy analysis clearly showed that probenecid inhibits the generation of ROS. Western blot analysis indicated that probenecid affects two downstream signaling molecules of ROS, cyclooxygenase 2 (COX-2) and c-Jun N-terminal kinase (JNK). These results indicate that probenecid inhibits ROS generation and exerts antiosteoclastogenic activity by inhibiting the COX-2 and JNK pathways. These results suggest that probenecid could potentially be used as a therapeutic agent to prevent bone resorption.

Network Pharmacology Deciphers the Action of Bioactive Polypeptide in Attenuating Inflammatory Osteolysis via the Suppression of Oxidative Stress and Restoration of Bone Remodeling Balance

“…ROS are critical intracellular signaling mediators that connect OC essential genes function, as well as the key regulator of cellular redox state that determines the post-translational modification of protein kinases and phosphatases in OC [ 46 , 47 ]. In the current study, the level of ROS in BMMs boosted obviously due to LPS stimulation, which is similar to other reports [ 48 ]. As the defense system, antioxidant enzymes, could balance the ROS formation, resulting in redox homeostasis within the cell [ 49 , 50 ].…”

Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

“…[56] Furthermore, it has been experimentally used for protection against nephrotoxicity. [35] Several explanations have been suggested through the inhibition of either the ROS/JNK pathway [34] or multidrug-resistance-associated protein 4 (MRP4). [57] Cheng and Kim reported that Prob inhibits COX-2 expression and uric acid concentration in metabolic bone disorders (i.e., osteoarthritis, osteoporosis, and rheumatic arthritis).…”

“…It is noteworthy that Prob can inhibit COX-2 expression and uric acid concentration in metabolic bone disorders. [34] To this end, the current study evaluated the use of Prob in BPH as a COX-2 inhibitor.…”

Neuroprotective Effects of the Pannexin-1 Channel Inhibitor: Probenecid on Spinal Cord Injury in Rats

“…Probenecid is a compound with a molecular weight of 285.36 Da, and its molecular formula is C 13 H 19 NO 4 S, which has been used for the treatment of gout clinically ( Cheng and Kim, 2020 ). Probenecid has been found to inhibit oxidative stress in neuronal cells ( Cheng and Kim, 2020 ) and also acts as a pannexin-1 channel inhibitor, which may inhibit the activation of inflammasomes ( Silverman et al, 2009 ), as well as being protective in a rat model of cognitive impairment ( Cheng and Kim, 2020 ). These reports suggest that probenecid is therapeutic for CNS injury.…”

“…Probenecid, a sulfonamide derivative approved for use in 1951, has been used to treat gout and its adverse effects, and pharmacokinetics have been intensively studied ( Baranova et al, 2004 ; Papadopoulos and Verkman, 2008 ). One study found that oxidative stress in nerve cells can be effectively inhibited by probenecid ( Cheng and Kim, 2020 ). Another study showed that probenecid also acts as a pannexin-1 channel inhibitor and may inhibit the activation of inflammasomes ( Silverman et al, 2009 ).…”