Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling
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Celecoxib Combined with Diacerein Effectively Alleviates Osteoarthritis in Rats via Regulating JNK and p38MAPK Signaling Pathways Zhifu Li,1,3 Dongdong Meng,2 Guangheng Li,1 Jianzhong Xu,1 Ke Tian,1 and Yu Li1
Abstract—Osteoarthritis (OA) has long been a difficult to overcome joint disease for medical workers. However, there is still a lack of effective treatments for OA. In the present study, we aimed to evaluate the treatment effect of celecoxib (CLX) combined with diacerein (DC) on OA and delineate the underlying molecular mechanism. The OA model was established by using rats, and OA rats were treated with either CLX alone, DC alone, and CLX combined with DC. The results showed that, as compared with a single treatment of CLX or DC, CLX combined with DC markedly attenuated OA and inhibited the levels of inflammatory mediators interleukin-1β and nitric oxide, improved bone cartilage metabolism, and suppressed chondrocyte apoptosis. Most importantly, CLX combined with DC significantly inactivated the c-Jun N-terminal kinases (JNK) signaling pathway by the inhibition of MEKK1 and MKK7, as detected by Western blot analysis. Furthermore, the protein expression of downstream genes of JNK, including activating-transcription factor (Atf-2), matrix metalloproteinase-13 (MMP-13), and cyclooxygenase (COX-2), were also significantly inhibited by CLX combined with DC as compared with single treatments. Furthermore, CLX combined with DC also effectively inhibits p38 mitogenactivated protein kinase and nuclear factor-κB signaling pathways. Taken together, our study suggests that CLX combined with DC has satisfactory treatment effects on OA via a stronger inhibitory effect on inflammatory signaling pathway. KEY WORDS: celecoxib; diacerein; JNK signaling pathway; osteoarthritis.
INTRODUCTION Osteoarthritis (OA) is a degenerative joint disease in elderly populations subjected to the impact of mechanical 1
Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, 450052 Zhengzhou, Henan, People’s Republic of China 2 Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, 450052 Zhengzhou, Henan, People’s Republic of China 3 To whom correspondence should be addressed at Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, 450052 Zhengzhou, Henan, People’s Republic of China. E-mail: [email protected] Abbreviations: OA, Osteoarthritis; MMP-13, Matrix metalloproteinase13; IL-1β, Interleukin-1β; TNF-α, Tumor necrosis factor α; CTX-II, Ctelopeptide fragments of type II collagen; MAPKs, Mitogen-activated protein kinases; JNK, c-Jun N-terminal kinases; Atf-2, Activating-transcription factor; COX-2, Cyclooxygenase; MAPK, Mitogen-activated protein kinase; NSAID, Non-steroidal anti-inflammatory drug; CLX, Celecoxib; DC, Diacerein; ELISA, Enzyme-linked immune sorbent assay; BMD, Bone mineral density
factors and biological factors. These harmful factors cause metabolic imbalance between chondroc
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