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Updated: Jan 23, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Multitarget-based cotreatment with cilostazol and celecoxib synergistically suppresses collagen-induced arthritis in
So Youn Park1, Yi Sle Lee1, Sang Yeob Lee2
1Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do 50612, Republic of Korea; Department of Pharmacology, School of Medicine, Pusan National University, Yangsan-si, Gyeongsangnam-do 50612, Republic of Korea.
Abstract:
Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 μM cilostazol and 0.3 μM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 μM) and celecoxib (0.3 μM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1β levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.
Insights
Cilostazol and celecoxib cotreatment synergistically reduced arthritis in mice by suppressing osteoclast formation and bone erosion. This combination therapy also increased anti-inflammatory interleukin-10 (IL-10) levels, suggesting a potent anti-arthritic effect.
Area of Science:
- Immunology and Rheumatology
- Pharmacology and Drug Discovery
Background:
- Cilostazol exhibits anti-inflammatory properties.
- Celecoxib is a selective COX-2 inhibitor offering an improved NSAID profile.
- Existing therapies for collagen-induced arthritis (CIA) have limitations.
Purpose of the Study:
- To evaluate the anti-arthritic potential of combining cilostazol with celecoxib in a CIA model.
- To investigate the role of interleukin-10 (IL-10) in the therapeutic action of this drug combination.
Main Methods:
- In vitro studies using RAW 264.7 cells and bone marrow-derived monocytes.
- Assessment of gene and protein expression related to osteoclastogenesis (RANK, OSCAR, DC-STAMP, cathepsin K, NFATc1).
- In vivo studies using DBA/1J mice with collagen-induced arthritis (CIA).
- Measurement of paw thickness, arthritis scores, cartilage degradation, and bone erosion.
Main Results:
- Cilostazol and celecoxib cotreatment synergistically suppressed RANKL-induced osteoclastogenic gene and protein expression in vitro.
- The combination therapy significantly reduced osteoclast formation and bone resorption.
- In CIA mice, cotreatment with cilostazol and celecoxib markedly reduced paw swelling, arthritis scores, cartilage damage, and bone erosion.
- Serum IL-10 levels were increased, and IL-1β levels were decreased by the cotreatment.
Conclusions:
- Combined low-dose cilostazol and celecoxib demonstrate synergistic anti-arthritic effects in collagen-induced arthritis.
- The therapeutic mechanism involves the suppression of osteoclastogenesis and modulation of inflammatory cytokines, particularly IL-10.
- This combination therapy holds promise for treating inflammatory arthropathies.
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