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

ABSTRACT: Wear particles may induce osteoclast formation and osteoblast inhibition that lead to periprosthetic osteolysis (PPOL) and subsequent aseptic loosening, which is the primary reason for total joint arthroplasty failure. Local bone renin-angiotensin system (RAS) has been found to participate in the pathogenic process of various bone-related diseases via promoting bone resorption and inhibiting bone formation. However, it remains unclear whether and how local bone RAS participates in wear-particle-induced PPOL. In this study, we investigated the potential role of RAS in titanium (Ti) particle-induced osteolysis in vivo and osteoclast and osteoblast differentiation in vitro. We found that the expressions of AT1R, AT2R and ACE in the interface membrane from patients with PPOL and in calvarial tissues from a murine model of Ti-particle-induced osteolysis were up-regulated, but the increase of ACE in the calvarial tissues was abrogated by perindopril. Moreover, perindopril mitigated the Ti-particle-induced osteolysis in the murine model by suppressing bone resorption and increasing bone formation. We also observed in RAW264.7 macrophages that Ang II promoted but perindopril suppressed Ti-particle-induced osteoclastogenesis, osteoclast-mediated bone resorption and expression of osteoclast-related genes. Meanwhile, Ang II enhanced but perindopril repressed Ti-particle-induced suppression of osteogenic differentiation and expression of osteoblast-specific genes in mouse bone marrow mesenchymal stem cells (BMSCs). In addition, local bone RAS promoted Ti-particle-induced osteolysis by increasing bone resorption and decreasing bone formation through modulating the RANKL/RANK and Wnt/β-catenin pathways. Taken together, we suggest that inhibition of RAS may be a potential approach to the treatment of wear-particle-induced PPOL.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC8264785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Small wear particles (0.1-10 ?m) in total joint replacement are generally considered as the major causative agent leading to periprosthetic inflammation and osteolysis. However, little is known about the roles of larger wear particles (10-100 ?m) in periprosthetic inflammation and osteolysis. Additionally, although ample studies demonstrated that increased oxidative stress is critically involved in particle-induced inflammation and osteolysis, detailed changes in antioxidant enzymes expression in the disease development remain largely unclear. Herein, we used a rat knee prosthesis model to assess effects of polyethylene (PE) particles (20-60 ?m) on the levels of oxidative stress markers such as malondialdehyde (MDA) and total antioxidant capacity (TAC) in blood plasma, and on the expression profiles of antioxidant enzymes in knee joint tissues. In combination with a forced-exercise intervention for all surgical rats, we found that the rat groups treated with both artificial joint and PE particles exhibited higher MDA levels and lower TAC levels, together with lower levels of physical activity and higher levels of inflammatory markers, than the sham group and the groups receiving artificial joint or PE particles alone at weeks 20-24 post-operatively. Dose-response relationships between the exposure to PE particles and the induction of oxidative stress and inflammation were also observed in the artificial joint/PE groups. Under such conditions, we unexpectedly found that most of antioxidant enzymes displayed pronounced up-regulation, with concomitant induction of inflammatory and osteoclast-inducing factors (including IL-1?, NF-?B and RANKL), in the artificial joint/PE groups as compared to the sham, artificial joint only, or PE only group. Only a few antioxidant enzymes including SOD2 and GPx2 showed down-regulation. Collectively, our findings demonstrate that implantation of artificial joint along with large PE particles synergistically trigger the induction of oxidative stress; however, down-regulation of many antioxidant enzymes may not necessarily occur during the disease development.

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

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