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Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE(2),
Zhi-feng Wei1, Xiao-lan Jiao, Ting Wang
1State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210009, China.
Aim:
To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms.
Methods:
AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR.
Results:
In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 proteins.
Conclusion:
NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE2, and MMP-13 expression via the p38/ERK/AKT/AP-1 pathway.
Insights
Norisoboldine (NOR) effectively reduces joint destruction in arthritis models by targeting key inflammatory markers. This natural compound shows promise in alleviating symptoms and preventing cartilage damage in adjuvant-induced arthritis (AIA).
Area of Science:
- Pharmacology
- Immunology
- Rheumatology
Background:
- Adjuvant-induced arthritis (AIA) is a rat model used to study inflammatory joint diseases.
- Radix Linderae contains norisoboldine (NOR), a potential therapeutic agent.
Purpose of the Study:
- To investigate the anti-arthritic effects of norisoboldine (NOR) in a rat model of adjuvant-induced arthritis (AIA).
- To elucidate the underlying molecular mechanisms by which NOR impacts joint destruction and inflammation.
Main Methods:
- Adjuvant-induced arthritis (AIA) was established in Sprague-Dawley rats.
- Rats were treated with varying doses of NOR or dexamethasone.
- Joint destruction was assessed using radiological imaging and histological analysis.
- Synovial fibroblast-like synoviocytes (FLS) were isolated and analyzed for protein and mRNA expression via ELISA, Western blotting, and RT-PCR.
Main Results:
- NOR treatment (15 and 30 mg/kg) significantly reduced paw swelling and arthritis scores in AIA rats.
- NOR (30 mg/kg) notably inhibited inflammatory cell infiltration and prevented bone and cartilage destruction.
- NOR suppressed serum and synovial levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE2, and MMP-13.
- In cultured FLS, NOR decreased the secretion of RANKL, IL-6, PGE2, and MMP-13 by inhibiting the p38/ERK/AKT/AP-1 signaling pathway.
Conclusions:
- Norisoboldine (NOR) demonstrates significant therapeutic potential in mitigating joint destruction associated with adjuvant-induced arthritis (AIA).
- NOR exerts its anti-arthritic effects by downregulating RANKL, IL-6, PGE2, and MMP-13 expression through the p38/ERK/AKT/AP-1 signaling pathway.
