Our long-range goal is to elucidate a mechanobiological mechanism responsible for periprosthetic bone loss. The long-term clinical success of hip arthoplasties is limited by prosthesis loosening which is characterized by ultrahigh molecular weight polyethylene (UHMWPE) wear particle-induced inflammatory bone loss and loss of host bone-prosthesis integration. Clinical observations have implicated UHMWPE wear particles, increased deformational strains and increased fluid pressure as possible causes for the implant loosening. The mechanobiological mechanism by which mechanical instability at the host bone-prosthesis interface amplifies UHMWPE wear particle-induced TNF-a signaling is likewise unknown. Our preliminary data indicate that clinically relevant UHMWPE wear particles, deformational strains and fluid shear stress activate calcineurin and NFATcl and induce the TNF-a gene in osteoblasts and macrophages. Our central hypothesis is that converging signals from UHMWPE wear particles and mechanical perturbation amplify TNF-a gene expression, augment osteoclastogenesis and promote the loss of osteoblastic phenotypes by co-activating the calcineurin/NFAT axis. We will simulate the periprosthetic mechanical perturbation in effective joint space by substrate deformation and by applying fluid flow patterns resembling a human gait cycle.
Specific Aims are 1) To verify that UHMWPE wear particles and mechanical perturbation amplify TNF- a production by co-activating the calcineurin/NFATd axis in osteoblasts, 2) To verify that UHMWPE wear particles and mechanical perturbation enhance RANKL-supported osteoclastogenesis by co-activating the calcineurin/NFATc1/TNF-a axis in macrophages, and 3) To determine the combinatorial effect of UHMWPE wear particles and mechanical perturbation on loss of osteoblastic phenotypes. In order to accomplish these aims, we will conduct a series of loss- and gain-of-function studies, dose response and time course experiments using pharmacological inhibitors, NFATcl siRNA and primary mouse osteoblasts derived from normal mice, calcineurin Ap -/- mice and TNF-a receptor -/- mice in the presence and absence of clinically relevant UHMWPE wear particles, deformational strains and fluid shear stress. It is envisioned that resrults from the proposed study will lead to the development of mechanism-based treatments for biomaterial- induced inflammatory bone loss in the presence of mechanical perturbations.
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