Combined effects of TNF‐α, IL‐1β, and HIF‐1α on MMP‐2 production in ACL fibroblasts under mechanical stretch: An in vitro study

Abstract

ABSTRACT:The dynamics between inflammatory factors, mechanical stress, and healing factors, in an intra-articular joint, are very complex after injury. Injury to intra-articular tissue [anterior cruciate ligament (ACL), synovium] results in hypoxia, accumulation of various pro-inflammatory factors, cytokines, and metalloproteases. Although the presence of increased amounts of matrix-metalloproteinases (MMP) in the joint fluid after knee injury is considered the key factor for ACL poor healing ability; however, the exact role of collective participants of the joint fluid on MMP-2 activity and production has not been fully studied yet. To investigate the combined effects of mechanical injury, inflammation and hypoxia induced factor-1a (HIF-1a) on induction of MMP-2; we mimicked the microenvironment of joint cavity after ACL injury. The results show that TNF-a and IL-1b elevate the activity of MMP-2 in a dose-and time-dependent manner. In addition, mechanical stretch further enhances the MMP-2 protein levels with TNF-a, IL-1b, and their mixture. CoCl 2 -induced HIF-1a (100 and 500 mM) also increases the levels and activity of MMP-2. Mechanical stretch has a strong additional effect on MMP-2 production with HIF-1a. Our results conclude that mechanical injury, HIF-1a and inflammatory factors collectively induce increased MMP-2 production in ACL fibroblasts, which was inhibited by NF-kB pathway inhibitor . ß

Tensile strength suppresses the osteogenesis of periodontal ligament cells in inflammatory microenvironments

“…Inflammatory cytokines, including IL-1β and TNF-α are involved in the up-regulation of MMPs (18,19). MMPs mediate connective tissue breakdown (11) and the degradation of numerous extracellular matrix proteins (42).…”

“…For instance, studies on human mesenchymal stem cells (hMSCs) revealed that expression of the master transcription factor for osteoblast differentiation, runt-related transcription factor 2 (RUNX2), was enhanced in the presence of media pre-conditioned with increased pro-inflammatory cytokine levels from classically activated monocytes (16,17). By contrast, inflammatory stimuli additionally induced factors that facilitate bone resorption, including matrix metalloproteinases (MMPs) in PDL fibroblasts (18) and the anterior cruciate ligament (19). In vitro (20) and in vivo (21,22) studies have demonstrated that alveolar bone resorption is closely associated with MMP production.…”

Enhanced Medial Collateral Ligament Healing Using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

“…Therefore, our results in the low dose MSC group demonstrating a smaller wound size and less creeping holds promise for stronger ligaments. Inflammatory cytokines, such as IL-1β, are known to activate matrix metalloproteinases (MMPs) in tendon and ligament leading to remodeling activity (32,33). The increased pro-inflammatory cytokines at day 5, including IL-1β, seen in the high dose MSC ligaments correlated with a larger healing region and active tissue seen later during healing.…”

MMP-2 and 9 in Chronic Kidney Disease

“…It has been proven that TNF-α can not only induce the expression of MMP-2 and 9 [41,42], but also promotes the activation of pro-MMP-2 [43] and thereby enhances the activity of MMP-2 [41,44]. Additionally, both TNF-α and TNF-β can promote the activation of pro-MMP-9 [45].…”