MiR‐377 inhibits wear particle‐induced osteolysis via targeting RANKL

Abstract

Periprosthetic osteolysis caused by wear particles is the main factor that affects the long‐term efficacy of artificial joint replacement, and macrophages play a vital role in the pathogenesis of periprosthetic osteolysis, while the potential mechanism underlying this is still unclear. To investigate the underlying role of miR‐377 in wear particle‐induced osteolysis (PIO), blood samples from patients undergoing arthroplasty were collected for analyzing the correlation between miR‐377 expression and the clinicopathological parameters of PIO. Peripheral blood macrophages were obtained to compare the miR‐377 and receptor activator of NF‐κB ligand (RANKL) expressions. Bone marrow macrophages (BMMs) following titanium (Ti) particle treatment and/or miR‐377 mimic transfection were used. The expressions of RANKL, pro‐inflammatory cytokines interleukin 6 (IL‐6) and tumor necrosis factor‐α (TNF‐α) and the osteoclast‐related molecules tartrate‐resistant acid phosphatase (TRAP) and cathepsin K (CTSK) were determined using real‐time polymerase chain reaction or western blotting or enzyme‐linked immunosorbent assay or TRAP staining, when appropriate. The interaction between miR‐377 and RANKL was assessed by luciferase reporter assay. The in vivo role of miR‐377 in PIO was evaluated using a mouse calvarial osteolysis model. There were significant differences in downregulated miR‐377 expression between the different numbers of particles in the joint prostheses. The Ti particle treatment increased pro‐inflammatory cytokine levels, downregulated RANKL and increased osteoclast activity in BMMs, while miR‐377 overexpression led to the opposite effect. Taken together, miR‐377 downregulated the target gene RANKL, resulting in PIO inhibition. MiR‐377 relieved PIO by negatively regulating RANKL.

Identification of Key Candidate Genes Related to Inflammatory Osteolysis Associated with Vitamin E-Blended UHMWPE Debris of Orthopedic Implants by Integrated Bioinformatics Analysis and Experimental Confirmation

“…TFs and microRNAs have been demonstrated to be important regulatory factors in the development of inflammatory osteolysis. 41 , 42 Thus, we constructed a TF-microRNA interaction regulatory network to show the potential interactions among TFs, DEGs, and microRNAs under wear debris-induced inflammatory conditions. As shown in the network, RELA was connected to 6 target genes (SOCS3, PTGS2, ICAM1, CXCL1, CCL5, CCL20) for TF nodes; NFKB1 was also connected to 6 target genes (SOCS3, PTGS2, ICAM1, CXCL1, CCL5, IL1RN).…”

Effects of the Local Bone Renin-Angiotensin System on Titanium-Particle-Induced Periprosthetic Osteolysis

“…It is well known that the RANKL/RANK and Wnt/β-catenin signaling pathways function in wear-particle-induced PPOL by promoting bone resorption and inhibiting bone formation ( Gohda et al, 2005 ; Nam et al, 2017 ; Park et al, 2017 ; Wang et al, 2021 ). RANKL is found expressed and upregulated in Ti-particle-induced osteolysis ( Zhu et al, 2017 ; Li W. et al, 2019 ; Ihn et al, 2019 ), and it is a major reason for osteoclastogenesis and bone resorption in PPOL ( Li W. et al, 2019 ). Combination of RANK with RANKL activates NF-κB signaling by recruiting adaptor molecules (such as TRAF6) and subsequently leads to the activation of C-FOS and NFATC1, which in turn up-regulates the expression of osteoclast-related genes and promotes the maturation and activation of osteoclasts ( Gohda et al, 2005 ; Park et al, 2017 ).…”