Fibroblast-Like-Synoviocytes Mediate Secretion of Pro-Inflammatory Cytokines via ERK and JNK MAPKs in Ti-Particle-Induced Osteolysis

Abstract

Biomaterials are designed to replace and augment living tissues in order to provide functional support to skeletal deformities. However, wear debris produced from the interfaces of metal implants initiates inflammatory bone loss, causing periprosthetic osteolysis. Lately, fibroblast-like synoviocytes (FLS) have been shown to play a role in wear-debris-induced osteolysis. Thus, here we have tried to understand the underlying mechanism of FLS involvement in wear-debris-induced osteolysis. Our results demonstrate that the effects of Ti particle (1:100 cell-to-Ti particle ratio) on FLS can induce Cox-2 expression and activate NFkB signaling. Moreover, the mRNA expression of pro-inflammatory cytokines such as IL-6, IL-8, IL-11, IL-1β, and TNFα was found to be elevated. However, among these pro-inflammatory cytokines, the mRNA and protein levels of only IL-6, IL-1β, and TNFα were found to be significantly higher. Ti particles activated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) as an early response in FLS. Co-inhibition of ERK and JNK signaling pathways by their specific inhibitors (PD9805 and SP600125, respectively) resulted in the suppression of mRNA and protein levels of IL-6, IL-1β, and TNFα in FLS. Taken together, targeting ERK and JNK MAPKs in FLS might provide a therapeutic option for reducing the secretion of bone-resorbing pro-inflammatory cytokines, thus preventing periprosthetic osteolysis.

Dual-specificity phosphatase 5 is a novel target gene of miR-216a-3p, inhibits the proliferation and invasion of fibroblast-like synoviocytes

“…The ERK signaling pathway is closely associated with several chronic in ammatory diseases, such as osteoarthritis, RA, and psoriatic arthritis [17,34]. The active form of ERK (p-ERK) can promote the expression of in ammatory genes [35].…”

“…The joint pathology was examined and scored as previously described [31]. The terminology used and units reported were based on international guidelines [34].…”

Effect of Alumina Particles on the Osteogenic Ability of Osteoblasts

“…Several researchers have shown that particular-sized wear debris initiates a composite pathology in periprosthetic osteolysis involving bone marrow stromal cells, osteoblasts, fibroblast cells, macrophages, monocytes, lymphocytes, and fibroblast-like synoviocytes. This often leads to an imbalance of osteoclastogenesis regulators such as RANKL and OPG [ 18 , 19 , 20 , 21 , 22 ]. Although bone loss by aseptic loosening of implants plays a critical role in bone resorption, the reduction in bone formation also appears to be a major factor contributing to bone resorption [ 23 , 24 ].…”

Strontium ion attenuates osteoarthritis through inhibiting senescence and enhancing autophagy in fibroblast-like synoviocytes

“…Due to the anatomical complexity of the joint, the pathogenesis of OA involves multiple processes, including synovial in ammation, articular cartilage loss, and a functional imbalance between osteoblasts and osteoclasts [8]. Among them, synovial in ammation is a serious risk factor [9]. With the increase of age, broblast-like synoviocytes (FLSs) show senescence and exhibit a senescence-associated secretory phenotype (SASP) [10][11][12].…”