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Inhibitory role of Annexin A1 in pathological bone resorption and therapeutic implications in periprosthetic osteolysis.

ABSTRACT: There is currently no therapy available for periprosthetic osteolysis, the most common cause of arthroplasty failure. Here, the role of AnxA1 in periprosthetic osteolysis and potential therapeutics were investigated. Reducing the expression of AnxA1 in calvarial tissue was found to be associated with increased osteolytic lesions and the osteolytic lesions induced by debris implantation were more severe in AnxA1-defecient mice than in wild-type mice. AnxA1 inhibits the differentiation of osteoclasts through suppressing NFκB signaling and promoting the PPAR-γ pathway. Administration of N-terminal-AnxA1 (Ac2-26 peptide) onto calvariae significantly reduced osteolytic lesions triggered by wear debris. These therapeutic effects were abrogated in mice that had received the PPAR-γ antagonist, suggesting that the AnxA1/PPAR-γ axis has an inhibitory role in osteolysis. The administration of Ac2-26 suppressed osteolysis induced by TNF-α and RANKL injections in mice. These findings indicate that AnxA1 is a potential therapeutic agent for the treatment of periprosthetic osteolysis.

SUBMITTER: Alhasan H

PROVIDER: S-EPMC9262976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions.

Project description:Aseptic loosening and periprosthetic osteolysis occur as a result of the biological response to particulate wear debris and are one of the leading causes of arthroplasty failure. Periprosthetic osteolysis originates from chronic inflammatory responses triggered by implant-derived particulate debris, which cause recruitment of cells, including macrophages, fibroblasts, lymphocytes and osteoclasts. These cells secrete proinflammatory and osteoclastogenic cytokines, exacerbating the inflammatory response. In addition to their direct activation by phagocytosis, there are contributing autocrine and paracrine effects that create a complex milieu within the periprosthetic space, which ultimately governs the development of osteolysis. Chronic cell activation may upset the delicate balance between bone formation and bone resorption leading to periprosthetic osteolysis. This article summarizes the genetic mechanisms underlying periprosthetic loosening and identifies potential therapeutic agents.

| S-EPMC3506691 | biostudies-literature

AnxA1 inhibits pathological bone resorption

Project description:We explored the functional role of AnxA1 in osteoclastogenesis and pathological bone loss associated with inflammatory osteolysis.

2022-05-23 | GSE183145 | GEO

AnxA1 inhibits pathological bone resorption

Project description:AnxA1 inhibits pathological bone resorption

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Targeting thymidine phosphorylase as a potential therapy for bone loss associated periprosthetic osteolysis

Project description:The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. TYMP was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

2021-06-10 | GSE171542 | GEO

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

Project description: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.

| S-EPMC8264785 | biostudies-literature

Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis.

Project description:Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA-seq for TYMP-induced-osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.

| S-EPMC8459589 | biostudies-literature

Periprosthetic bone loss: diagnostic and therapeutic approaches.

Project description:Total joint replacement surgery is being performed on an increasingly large part of the population. Clinical longevity of implants depends on their osseointegration, which is influenced by the load, the characteristics of the implant and the bone-implant interface, as well as by the quality and quantity of the surrounding bone. Aseptic loosening due to periprosthetic osteolysis is the most frequent known cause of implant failure. Wear of prosthetic materials results in the formation of numerous particles of debris that cause a complex biological response. Dual-energy X-ray Absorptiometry (DXA) is regarded as an accurate method to evaluate Bone Mineral Density (BMD) around hip or knee prostheses. Further data may be provided by a new device, the Bone Microarchitecture Analysis (BMA), which combines bone microarchitecture quantification and ultra high resolution osteo-articular imaging. Pharmacological strategies have been developed to prevent bone mass loss and to extend implant survival. Numerous trials with bisphosphonates show a protective effect on periprosthetic bone mass, up to 72 months after arthroplasty. Strontium ranelate has been demonstrated to increase the osseointegration of titanium implants in treated animals with improvement of bone microarchitecture and bone biomaterial properties.

| S-EPMC4304431 | biostudies-literature

Periprosthetic osteolysis after total wrist arthroplasty.

Project description:Background and Literature Review Periprosthetic osteolysis (PPO) after second- or third-generation total wrist arthroplasty (TWA), with or without evident loosening of the implant components, has previously been reported in the literature, but rarely in a systematic way. Purpose The purpose of this study was to analyze the prevalence, location, and natural history of PPO following a TWA and to determine whether this was associated with prosthetic loosening. Patients and Methods We analyzed 44 consecutive cases in which a RE-MOTION TWA (Small Bone Innovations Inc., Morrisville, PA, USA) had been done. Results We found significant periprosthetic radiolucency (more than 2 mm in width) at the radial component side in 16 of the cases and at the carpal component side in 7. It developed gradually juxta-articularly around the prosthetic components regardless of the primary diagnosis, and seemed to stabilize in most patients after 1-3 years. In a small percentage of the patients, the periprosthetic area of bone resorption was markedly larger. In general, radiolucency was not related to evident loosening of the implant components, and only five carpal components and one radial had subsided or tilted. Conclusion Periprosthetic loosening is frequent following a TWA. In our series it was not necessarily associated with implant loosening and seemed to stabilize within 3 years. Close and continued observation is, however, recommended. Level of Evidence Therapeutic IV.

| S-EPMC4078145 | biostudies-other

Mechanically Induced Periprosthetic Osteolysis: A Systematic Review.

Project description:Background:Peri-prosthetic bone loss can result from chemical, biological, and mechanical factors. Mechanical stimulation via fluid pressure and flow at the bone-implant interface may be a significant cause. Evidence supporting mechanically induced osteolysis continues to grow, but there is no synthesis of published clinical and basic science data. Questions/Purposes:We sought to review the literature on two questions: (1) What published evidence supports the concept of mechanically induced osteolysis? (2) What is the proposed mechanism of mechanically induced osteolysis, and does it differ from that of particle-induced osteolysis? Methods:A systematic review was performed of the PubMed and Web of Science databases. Additional relevant articles were recommended by the senior authors based on their expert opinion. Abstracts were reviewed and the manuscripts pertaining to the study questions were read in full. Studies showing support of mechanically induced osteolysis were quantified and findings summarized. Results:We identified 49 articles of experimental design supporting the hypothesis that mechanical stimulation of peri-prosthetic bone from fluid pressure and flow can induce osteolysis. While the molecular mechanisms may overlap with those implicated in particle-induced osteolysis, mechanically induced osteolysis appears to be mediated by distinct and parallel pathways. Conclusions:The role of mechanical stimuli is increasingly recognized in the pathogenesis of peri-prosthetic osteolysis. Current research aims to elucidate the molecular mechanisms to better target therapeutic interventions.

| S-EPMC6778158 | biostudies-literature

Annexin A1 regulates neutrophil clearance by macrophages in the mouse bone marrow.

Project description:Under homeostatic conditions, a proportion of senescent CXCR4(hi) neutrophils home from the circulation back to the bone marrow, where they are phagocytosed by bone marrow macrophages. In this study, we have identified an unexpected role for the anti-inflammatory molecule annexin A1 (AnxA1) as a critical regulator of this process. We first observed that AnxA1(-/-) mice have significantly increased neutrophil numbers in their bone marrow while having normal levels of GM and G colony-forming units, monocytes, and macrophages. Although AnxA1(-/-) mice have more neutrophils in the bone marrow, a greater proportion of these cells are senescent, as determined by their higher levels of CXCR4 expression and annexin V binding. Consequently, bone marrow neutrophils from AnxA1(-/-) mice exhibit a reduced migratory capacity in vitro. Studies conducted in vitro also show that expression of AnxA1 is required for bone marrow macrophages, but not peritoneal macrophages, to phagocytose apoptotic neutrophils. Moreover, in vivo experiments indicate a defect in clearance of wild-type neutrophils in the bone marrow of AnxA1(-/-) mice. Thus, we conclude that expression of AnxA1 by resident macrophages is a critical determinant for neutrophil clearance in the bone marrow.

| S-EPMC3250241 | biostudies-literature

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