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Particle-induced osteolysis, which by definition is an aseptic inflammatory reaction to implant-derived wear debris eventually leading to local bone destruction, remains the major reason for long-term failure of orthopedic endoprostheses. Fetuin-A, a 66kDa glycoprotein with diverse functions, is found to be enriched in bone. Besides being an important inhibitor of ectopic calcification, it has been described to influence the production of mediators of inflammation. Furthermore, a regulatory role in bone metabolism has been assigned. In the present study, the influence of a single dose of bovine fetuin-A, intraperitoneally injected in mice subjected to particle-induced osteolysis of the calvaria, was analyzed. Twenty-eight male C57BL/6 mice, twelve weeks of age, were randomly divided into four groups. Groups 2 and 4 were subjected to ultra-high molecular weight polyethylene (UHMWPE) particles placed on their calvariae while groups 1 and 3 were sham-operated. Furthermore, groups 3 and 4 received a single intraperitoneal injection of 20mg bovine fetuin-A while groups 1 and 2 were treated with physiologic saline. After 14days calvarial bone was qualitatively and quantitatively assessed using microcomputed tomography (μCT) and histomorphometrical approaches. Application of fetuin-A led to a reduction of particle-induced osteolysis in terms of visible osteolytic lesions and eroded bone surface. The reduction of bone thickness and bone volume, as elicited by UHMWPE, was alleviated by fetuin-A. In conclusion, fetuin-A was found to exert an anti-resorptive effect on particle-induced osteolysis in-vivo. Thus, fetuin-A could play a potentially osteoprotective role in the treatment of bone metabolic disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: This study investigates the impact of alpha-CGRP on bone metabolism after implantation of polyethylene particles. alpha-CGRP knockout mice showed less osteolysis compared with wildtype mice. The local neurogenic microenvironment might be a crucial factor in particle-induced osteolysis., Introduction: Periprosthetic osteolysis is the major reason for aseptic loosening in joint arthroplasty. This study aimed to investigate the potential impact of alpha-calcitonin gene-related peptide (alpha-CGRP) deficiency on bone metabolism under conditions of polyethylene particle-induced osteolysis., Materials and Methods: We used the murine calvarial osteolysis model based on polyethylene particles in 14 C57BL 6 mice and 14 alpha-CGRP-deficient mice divided into four groups of 7 mice each. Groups 1 (C57BL/J 6) and 3 (alpha-CGRP knockout) received sham surgery, and groups 2 (C57BL/J 6) and 4 (alpha-CGRP knockout) were treated with polyethylene particles. Qualitative and quantitative 3D analyses were performed using microCT. In addition, bone resorption was measured within the midline suture by histological examination. The number of osteoclasts was determined by counting the TRACP(+) cells. Calvarial bone was tested for RANKL expression by RT-PCR and immunocytochemistry., Results: Bone resorption was significantly reduced in alpha-CGRP-deficient mice compared with their corresponding wildtype C57BL 6 mice as confirmed by histomorphometric data (p < 0.001) and microCT (p < 0.01). Osteoclast numbers were significantly reduced in group 3 and the particle subgroup compared with group 1 (p < 0.001). We observed a >3-fold increase of basal RANKL mRNA levels within group 1 compared with group 3. Additional low RANKL immunochemistry staining was noted in groups 3 and 4., Conclusions: In conclusion, alpha-CGRP knockout mice did not show the expected extended osteolysis compared with wildtype mice expressing alpha-CGRP. One of the most reasonable explanations for the observed decrease in osteolysis could be linked to the osteoprotegerin (OPG)/RANK/RANKL system in alpha-CGRP-deficient animals. As a consequence, the fine tuning of osteoclasts mediating resorption in alpha-CGRP-null mice may be deregulated.

Aseptic loosening is the major cause of total joint replacement failure. Substance P (SP) is a neurotransmitter richly distributed in sensory nerve fibers, bone, and bone-related tissue. The purpose of this study was to investigate the potential impact of SP on bone metabolism in polyethylene particle-induced osteolysis. We utilized the murine calvarial osteolysis model based on ultrahigh molecular weight polyethylene (UHMWPE) particles in 14 wild-type mice (C57BL/J6) and 14 SP-deficient mice. Group 1 (C57BL/J 6) and group 3 (SP-knockout) received sham surgery, and group 2 (C57BL/J6) and group 4 (SP-knockout) were treated with polyethylene particles. Analytical methods included three-dimensional micro-computed tomographic (micro-CT) analysis and histomorphometry. Bone resorption was measured within the midline suture. The number of osteoclasts was determined by counting the tartrate-resistant acid phosphatase-positive cells. UHMWPE-particle treated SP-deficient mice showed significantly reduced osteolysis compared to wild-type mice, as confirmed by histomorphometry (P < 0.001) and micro-CT (P = 0.035). Osteoclast numbers were significantly reduced in groups 3 and 4 compared to groups 1 and 2 (P < 0.001). Unexpectedly, SP-deficient mice (group 3) showed a significantly increased absolute bone mass compared to wild-type mice (group 1) (P = 0.02). The findings of our murine calvaria model lead to the assumption that SP is a promoter in particle-induced osteolysis. The pathophysiology of aseptic loosening is complex, and neuropeptides are not solely responsible for the progress of implant loosening; however, we conclude that there could be coherence between neurotransmitters and particle-induced osteolysis in patients with aseptic loosening.

An ongoing unraveling of the molecular mechanisms in aseptic loosening of hip arthroplasty has opened up novel potential pharmacological interventions. In this study the antiresorptive effects of the bisphosphonate zoledronate and the statin simvastatin on ultra high molecular weighted polyethylene (UHMWPE) particle-induced osteolysis were compared. Two previous studies of our group based on the murine calvarial model of UHWMPE particle-induced osteolysis were pooled to form four study groups. Animals in group I (n=14) underwent sham surgery only. In groups II (n=14), III (n=7) and IV (n=7) UHMWPE particles were implanted on the calvariae. Animals in groups III and IV were additionally treated with zoledronate (single 25 microg/kg s.c. injection) and simvastatin (120 mg/day p.o. for 14 days), respectively. After two weeks, calvaria were processed for undecalcified histomorphometry. Bone resorption was measured using Giemsa staining. Osteoclast numbers were determined using TRAP-staining. UHMWPE particle implantation resulted in a grossly pronounced osteolytic activity with significantly increased values of bone resorption (p < 0.001) and osteoclast numbers (p < 0.001). Additional treatment with zoledronate or simvastatin counteracted the particle-induced effects. A comparison of the two medical treatments revealed no statistically significant differences in bone resorption (p = 0.63) and osteoclast numbers (p = 0.41). A single dose of the bisphosphonate zoledronate decreased UHMWPE particle-induced osteolysis in a murine calvarial model as effectively as a daily treatment with simvastin. Both drug groups may have a preventive and therapeutic role as antiresorptive agents in wear particle-induced bone resorption following total joint replacement.