Polyethylene Particle–Induced Bone Resorption in α-Calcitonin Gene–Related Peptide–Deficient Mice

Abstract

This study investigates the impact of ␣-CGRP on bone metabolism after implantation of polyethylene particles. ␣-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 ␣-calcitonin gene-related peptide (␣-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 ␣-CGRP-deficient mice divided into four groups of 7 mice each. Groups 1 (C57BL/J 6) and 3 (␣-CGRP knockout) received sham surgery, and groups 2 (C57BL/J 6) and 4 (␣-CGRP knockout) were treated with polyethylene particles. Qualitative and quantitative 3D analyses were performed using CT. 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 ␣-CGRP-deficient mice compared with their corresponding wildtype C57BL 6 mice as confirmed by histomorphometric data (p < 0.001) and CT (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, ␣-CGRP knockout mice did not show the expected extended osteolysis compared with wildtype mice expressing ␣-CGRP. One of the most reasonable explanations for the observed decrease in osteolysis could be linked to the osteoprotegerin (OPG)/RANK/RANKL system in ␣-CGRP-deficient animals. As a consequence, the fine tuning of osteoclasts mediating resorption in ␣-CGRP-null mice may be deregulated.

Calcitonin Gene-Related Peptide Modulates the Production of Pro-Inflammatory Cytokines Associated with Periprosthetic Osteolysis by THP-1 Macrophage-Like Cells

“…In previous studies on an animal model of particle-induced osteolysis, we were able to show an inhibitory effect of CGRP on ultra-high-molecular-weight polyethylene (UHMWPE) particle-induced bone resorption [33,34]. Furthermore, we proved the observed osteoprotective effect of CGRP on particle-induced osteolysis in previous in vitro studies using human osteoblasts [35,36], suggesting its ability to reverse the catabolic effects elicited by UHMWPE particles.…”

The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis

“…In the present study, treatment with UHMWPE particles was associated with distinct signs of osteolysis in WT and CTR-KOs. This is in contrast to findings in a-CGRP-deficient mice, where we discovered significantly reduced osteolysis compared to their corresponding WT mice [13]. The reduction in osteolysis in a-CGRP-deficient mice could, however, have been attributed to a compensatory effect induced by the remaining CT, since a-CGRP is generated by alternative splicing from the Calca gene, which also encodes CT.…”

“…osteolysis was found in a-CGRP-deficient mice. This favored the theory of an a-CGRP-dependent effect on bone turnover in the process of aseptic loosening [13,15]. However, the observed reduction in PIO in a-CGRP-deficient mice could have been attributed to a compensatory effect of CT. Huebner et al [16] reported the dual action of CT, as an inhibitor of both bone formation and bone resorption, which could be highly relevant in conditions associated with increased bone resorption, such as PIO.…”

“…In the present study, the previously described murine calvaria model of UHMWPE particle-induced osteolysis [12,13,19,20] was used in 10 male mice with a global CTR deletion (CTR-KO) generated using the Cre/loxP system and with a genetic background of C57BL/6, as reported by Davey et al [7]. For comparative analysis, 10 male C57BL/6J wildtype (WT) mice, aged 3 months, obtained from Jackson Laboratories (Bar Harbor, Maine, USA), were similarly treated.…”

“…In an attempt to assess the impact of CT/a-CGRP in the presence of UHMWPE particles, mice with an isolated or combined deficiency of a-CGRP and CT were studied [11][12][13]. While UHMWPE particles revealed pronounced osteolysis in wild-type mice, different observations in a-CGRP-and CT-deficient mice were made [14].…”