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.
|Fischer, Charla R; Mikami, Maya; Minematsu, Hiroshi et al. (2017) Calreticulin inhibits inflammation-induced osteoclastogenesis and bone resorption. J Orthop Res 35:2658-2666|
|Worthley, Daniel L; Churchill, Michael; Compton, Jocelyn T et al. (2015) Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269-84|
|Patel, Neel; Nizami, Saqib; Song, Lee et al. (2015) CA-074Me compound inhibits osteoclastogenesis via suppression of the NFATc1 and c-FOS signaling pathways. J Orthop Res 33:1474-86|
|Kim, Kyung Ok; Hsu, Anny C; Lee, Heon Goo et al. (2014) Proteomic identification of 14-3-3? as a linker protein between pERK1/2 inhibition and BIM upregulation in human osteosarcoma cells. J Orthop Res 32:848-54|
|Carrisoza-Gaytan, Rolando; Liu, Yu; Flores, Daniel et al. (2014) Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). Am J Physiol Renal Physiol 307:F195-204|
|Lee, Heon Goo; Hsu, Anny; Goto, Hana et al. (2013) Aggravation of inflammatory response by costimulation with titanium particles and mechanical perturbations in osteoblast- and macrophage-like cells. Am J Physiol Cell Physiol 304:C431-9|
|Lee, Heon Goo; Minematsu, Hiroshi; Kim, Kyung Ok et al. (2011) Actin and ERK1/2-CEBP? signaling mediates phagocytosis-induced innate immune response of osteoprogenitor cells. Biomaterials 32:9197-206|
|Minematsu, Hiroshi; Shin, Mike J; Celil Aydemir, Ayse B et al. (2011) Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages. Cell Signal 23:1785-93|
|Seo, Sung Wook; Lee, Daniel; Minematsu, Hiroshi et al. (2010) Targeting extracellular signal-regulated kinase (ERK) signaling has therapeutic implications for inflammatory osteolysis. Bone 46:695-702|
|Celil Aydemir, Ayse B; Minematsu, Hiroshi; Gardner, Thomas R et al. (2010) Nuclear factor of activated T cells mediates fluid shear stress- and tensile strain-induced Cox2 in human and murine bone cells. Bone 46:167-75|
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