Abstract
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.
Highlights
Osteoarthritis (OA) is the main cause of incapacity in elderly pop‐ ulation, other factors such as obesity, metabolism and previous joint damage generate patients’ disability
As we previously reported the implication of the proinflammatory mediators IL‐1β and fibronectin fragments (Fn‐fs) in ADAMTS‐7 and ‐12 production,[5] we evaluated the involvement of Runx[2] and Wnt/β‐catenin signalling in the expression of ADAMTS‐7 and ‐12 by synovial fibroblasts (SF) stimulated with these two proinflammatory mediators
OA is primarily characterized by chondrocytes degradation, other cells including SF intervene through the activation of different biochemical pathways that trig‐ ger the breakdown of the cartilage extracellular matrix (ECM) mediated by proteinases.[5,23]
Summary
Osteoarthritis (OA) is the main cause of incapacity in elderly pop‐ ulation, other factors such as obesity, metabolism and previous joint damage generate patients’ disability. | 3975 proteases in the osteoarthritic degradation of the ECM, including matrix metalloproteinases (MMPs) and several ADAMTS (a disinteg‐ rin and metalloproteinase with thrombospondin motifs), such as the aggrecanases ADAMTS‐4 and ‐5.2,3 Given the limited regeneration capacity of the articular cartilage, prevention of its damage, results crucial to reduce disease severity. In this sense, the control of inflam‐ mation and proliferation of the synovial membrane in OA patients could contribute to cartilage protection. We studied the involvement of ADAMTS‐7 and ‐12, and their signalling pathways in the regulation of COMP degradation in the cartilage‐SF interaction
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