Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast-derived ADAMTS-7 and -12.
Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. The knowledge of this network would contribute to selective target patho...
| Autores: | , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2019 |
| País: | España |
| Institución: | Servizo Galego de Saúde (SERGAS) |
| Repositorio: | RUNA. Repositorio da Consellería de Sanidade e Sergas |
| OAI Identifier: | oai:runa.sergas.gal:20.500.11940/15942 |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533528/pdf/JCMM-23-3974.pdf https://www.ncbi.nlm.nih.gov/pubmed/30903650 http://hdl.handle.net/20.500.11940/15942 |
| Access Level: | acceso abierto |
| Palabra clave: | Wnt Signaling Pathway Humans Fibroblasts Cartilage Oligomeric Matrix Protein Interleukin-1beta Extracellular Matrix Core Binding Factor Alpha 1 Subunit Synovial Membrane Osteoarthritis Fibronectins Aged Cartilage anciano membrana sinovial fibronectinas fibroblastos cartílago matriz extracelular subunidad alfa 1 del factor de unión central proteína oligomérica de la matriz del cartílago interleucina-1beta humanos osteoartritis vía de señalización Wnt CHUAC INIBIC |
| Sumario: | Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. The knowledge of this network would contribute to selective target pathological conditions. In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial fibroblasts (SF), would prevent cartilage damage. Thus, we studied the contribution of ADAMTS-7 and -12 from SF to cartilage oligomeric matrix protein (COMP) degradation, and the signalling pathways involved in their expression. We report for the first time in SF, the involvement of ERK-Runx2 axis and Wnt/beta-catenin signalling in ADAMTS-12 and ADAMTS-7 expressions, respectively, with the subsequent consequences in COMP degradation from cartilage extracellular matrix. After stimulation with IL-1beta or fibronectin fragments, we showed that ERK inhibition decreased Runx2 activation and ADAMTS-12 expression in OA-SF, also reducing Fn-fs-induced COMP degradation. Blockage of Wnt signalling by DKK1 reduced ADAMTS-7 and COMP degradation in OA-SF as well. In addition, Wnt7B expression was induced by IL-1beta and by itself, also increasing ADAMTS-7. Our results could contribute to the development of disease-modifying OA drugs targeting ADAMTS-7 and -12 for the prevention of extracellular matrix components degradation like COMP. |
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