Polyethylene Particle-Induced Bone Resorption in Substance P-Deficient Mice

Abstract

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.

Evolving Concepts in Neurogenic Osteoporosis

“…However, mice in which the gene for SP has been deleted are reported to have normal bone [44], although a detailed description of bone phenotypes in this strain has not been reported. The possibility that SP may play roles in bone metabolism in pathologic states is suggested by findings that its deletion enhanced bone loss in a model of failure for orthopedic prostheses [45]. Also, in a young rat model of SCI, a significant increase of 19% and 18% was noted in SP-immunoreactive nerve fibers at 3 and 6 weeks, respectively, in SCI compared with control animals, perhaps adversely effecting bone mass [46].…”

Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions

“…Substance P belongs to the tachykinin family and interacts with the neurokinin 1 receptor (NK 1 R). Wedemeyer and colleagues 25 used the murine calvarial osteolysis model based on UHMWPE particles in 14 wild-type mice (C57BL/J6) and 14 SPdeficient mice. Groups 1 (C57BL/J6) and 3 (SP-knockout) received sham surgery, and groups 2 (C57BL/J6) and 4 (SP-knockout) were treated with PE particles.…”

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

“…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.…”

“…After exposing the periosteum using a 10 mm incision over the calvarian sagittal midline suture, the mice of groups 2 and 4 received approximately 30 ll (2 Â 10 8 particles per ml) of dried UHMWPE particles implanted periostally, whereas groups 1 and 3 underwent sham surgery without particle implantation. The incision was closed identically in all groups using a 4-0 Ethilon skin suture (Ethicon, Sommerville, NJ, USA) [20]. After 14 days, the animals were sacrificed in a CO 2 chamber.…”