Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Abstract

Current description of osteoarthritis includes the involvement of synovial inflammation. Studies contributing to understanding the mechanisms of cross-talk and feedback among the joint tissues could be relevant to the development of therapies that block disease progression. During osteoarthritis, synovial fibroblasts exposed to anomalous mechanical forces and an inflammatory microenvironment release factors such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) metalloproteinases that mediate tissue damage and perpetuate inflammation. We therefore studied the production of ADAMTS by synovial fibroblasts and their contribution to cartilage degradation. Moreover, we analyzed the implication of two mediators present in the osteoarthritis joint, IL-1b as proinflammatory cytokine, and 45-kDa fibronectin fragments as products of matrix degradation. We reported that synovial fibroblasts constitutively express and release ADAMTS 4, 5, 7, and 12. Despite the contribution of both mediators to the stimulation of Runx2 and Wnt/b-catenin signaling pathways, as well as to ADAMTS expression, promoting the degradation of aggrecan and cartilage oligomeric matrix protein from cartilage, fibronectin fragments rather than IL-1b played the major pathological role in osteoarthritis, contributing to the maintenance of the disease. Moreover, higher levels of ADAMTS 4 and 7 and a specific regulation of ADAMTS-12 were observed in osteoarthritis, suggesting them as new potential therapeutic targets. Therefore, synovial fibroblasts provide the biochemical tools to the chronicity and destruction of the osteoarthritic joints. (Am J Pathol 2016, -: 1e13; http:// dx

FRI0016 Involvement of runx-2 and β-catenin signaling in the production of adamts-7 and adamts-12 in osteoarthritic synovial fibroblasts

“…Besides, ERK inhibitor decreased ADAMTS-12 mRNA and protein exclusively in OA-SF. Conclusions: We reported that ADAMTS-7 protein expression is higher in OA-SF compared to HD confirming previous data at mRNA level (1). As DKK decreased ADAMTS-7, Wnt-β-catenin signaling seems to be implicated in its expression.…”

“…As Runx2 and β-catenin are two transcription factors involved in chondrocytes metabolism and OA pathology (2-5), we studied whether these factors are implicated in the production of ADAMTS-7 and 12 in SF. Moreover, we analyzed the induction by two inflammatory mediators present in OA joints: interleukin-1β (IL-1β), and fibronectin fragments (Fn-fs), previously described in ADAMTS expression (1). Objectives: To elucidate the signaling pathways involved in the production of ADAMTS-7 and -12 in healthy donors (HD) -and OA-SF.…”

Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

“…Some studies consider ADAMTS4 the main factor implicated in OA because its levels are increased in the cartilage of these patients, correlating with a greater degradation of this tissue. However, other authors reported ADAMTS4 and -5 expressions in cartilage and SF, where ADAMTS5 was more expressed in SF from healthy donors (HD) than in OA, while ADAMTS4 gene expression was similar in both [33,50]. In addition, in vitro studies have shown that ADAMT5 activity is higher than that of ADAMTS4 [142].…”

“…In this way, they are able to activate different signaling pathways such as the MAPK pathway or transcription factors such as NF-κB or AP-1 [9,[27][28][29][30][31]. In addition, they are able to establish a positive feedback with the Wnt/β-catenin pathway through integrins and MAPK signaling [32,33].…”

Krüppel-Like Factor 2 Regulates Degradation of Type II Collagen by Suppressing the Expression of Matrix Metalloproteinase (MMP)-13

“…Our results demonstrate that KLF2 inhibits type Ⅱ collagen by suppressing the expression of MMP-13, suggesting the potential role of KLF2 in the treatment of OA. In addition to MMPs, aggrecanases and other catabolic enzymes have been considered to play an important role in the extracellular matrix, both directly and indirectly [27, 28]. Investigations of the effects of KLF2 on the activity of these enzymes are ongoing in our laboratory.…”