Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast-derived ADAMTS-7 and -12.
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Identificadores
URI: http://hdl.handle.net/20.500.11940/15942
PMID: 30903650
DOI: 10.1111/jcmm.14283
ISSN: 1582-1838
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Fecha de publicación
2019Título de revista
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Tipo de contenido
Artigo
DeCS
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 WntMeSH
Wnt Signaling Pathway | Humans | Fibroblasts | Cartilage Oligomeric Matrix Protein | Interleukin-1beta | Extracellular Matrix | Core Binding Factor Alpha 1 Subunit | Synovial Membrane | Osteoarthritis | Fibronectins | Aged | CartilageResumen
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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