Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast-derived ADAMTS-7 and -12

© 2019 The Authors.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/β-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-1β 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-1β 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.This work has been supported by Instituto de Salud Carlos III, Spain, cofinanced by FEDER, European Union: RETICS program, Red de Investigación en Inflamación y Enfermedades Reumáticas (RD16/0012/0002 RD16/0012/0006 and RD16/0012/0008), the project SAF 2017‐82940‐R, and the projects PI17/00027 and PI16/2124 integrated in the National Plan for Scientific Program, Development and Technological Innovation and Funded by ISCIII‐General Subdirection of Assessment and Promotion of Research‐European Regional Development Fund (FEDER) “A way of making Europe”. MFM was supported by CIBER (CB06/01/0040)