RESUMO
The osteoarthritis (OA) progression is now considered to be related to inflammation. Anemonin (ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL-1ß/NF-κB pathway activation. Destabilization of the medial meniscus (DMM) was performed in 10-week-old male C57BL/6J mice. ANE was then intra-articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin-1ß (IL-1ß) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE -treated mice compared with vehicle-treated mice. ANE decreased the expressions of matrix metalloproteinase-13 (MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL-1ß ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL-1ß/NF-κB pathway activation.
Assuntos
Anti-Inflamatórios/farmacologia , Cartilagem Articular/efeitos dos fármacos , Furanos/farmacologia , Interleucina-1beta/genética , NF-kappa B/genética , Osteoartrite/tratamento farmacológico , Proteína ADAMTS5/antagonistas & inibidores , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Agrecanas/agonistas , Agrecanas/genética , Agrecanas/metabolismo , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Colágeno Tipo X/genética , Colágeno Tipo X/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Injeções Intra-Articulares , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Cultura Primária de Células , Transdução de Sinais , Técnicas de Cultura de TecidosRESUMO
Transforming growth factor (TGF)ß regulates the anabolic metabolism of articular cartilage and prevents cartilage degradation. TGFß1 influences cellular proliferation, differentiation and the extracellular matrix through activation of the extracellular signalregulated kinase (ERK)1/2 and Smad2/3 signaling pathways. However, it has remained to be fully elucidated precisely how the ERK1/2 and Smad2/3 signaling pathways mediate anabolic processes of articular cartilage. The present study investigated how ERK1/2 and Smad2/3 signaling mediate TGFß1stimulated type II collagen and aggrecan expression in rat chondrocytes. The results confirmed that TGFß1 stimulates type II collagen and aggrecan expression in rat chondrocytes, and furthermore, that the ERK1/2 and Smad2/3 signaling pathways were activated by TGFß1. Conversely, the TGFß receptor I (ALK5) kinase inhibitor SB525334 significantly impaired TGFß1induced type II collagen and aggrecan expression, coinciding with a reduction of ERK1/2 and Smad3 phosphorylation. In addition, TGFß1induced type II collagen and aggrecan expression were significantly suppressed by ERK1/2 inhibitor PD98059. Similarly, TGFß1stimulated type II collagen and aggrecan expression were decreased in the presence of a Smad3 phosphorylation inhibitor SIS3. Therefore, the present study demonstrated that the ERK1/2 and Smad2/3 signaling pathways regulate type II collagen and aggrecan expression in rat chondrocytes.
