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Ormsby R.T.,University of Adelaide | Cantley M.,University of Adelaide | Cantley M.,Myeloma Research Laboratory | Kogawa M.,University of Adelaide | And 4 more authors.
Acta Biomaterialia | Year: 2016

Periprosthetic osteolysis (PO) leading to aseptic loosening, is the most common cause of failure of total hip replacement (THR) in the mid- to long-term. Polyethylene (PE) particulates from the wear of prosthesis liners are bioactive and are implicated in the initiation and or progression of osteolysis. Evidence exists that cells of the osteoblast/osteocyte lineage are affected by PE particles and contribute to the catabolic response by promoting osteoclastic bone resorption. In this study, we hypothesised that osteocytes contribute directly to PO by removing bone from their perilacunar matrix. Osteocyte responses to ultra-high molecular weight PE (UHMWPE) particles were examined in vitro in human primary osteocyte-like cultures, in vivo in the mouse calvarial osteolysis model, and in the acetabulum of patients undergoing revision total hip replacement (THR) surgery for PO. Osteocytes exposed to UHMWPE particles showed upregulated expression of catabolic markers, MMP-13, carbonic anhydrase 2 (CA2), cathepsin K (CTSK) and tartrate resistant acid phosphatase (TRAP), with no effect on cell viability, as assessed by Caspase 3 activity. Consistent with this catabolic activity causing perilacunar bone loss, histological analysis of calvarial sections from mice exposed to UHMWPE revealed a significant (p <. 0.001) increase in osteocyte lacunar area (Lac.Ar) compared to sham-operated animals. Furthermore, acetabular biopsies from patients with PO also showed significantly (p <. 0.001) increased osteocyte lacunar size in trabecular bone adjacent to PE particles, compared with osteocyte lacunar size in bone from primary THR patients. Together, these findings suggest a previously unrecognised action of UHMWPE wear particles on osteocytes, which directly results in a loss of osteocyte perilacunar bone. This action may exacerbate the indirect pro-osteoclastic action of UHMWPE-affected osteocytes, previously shown to contribute to aseptic loosening of orthopaedic implants. Statement of Significance: This study addresses the clinical problem of periprosthetic osteolysis, bone loss in response to polyethylene wear particles derived from materials used in orthopaedic implants. Periprosthetic osteolysis has been thought to be due largely to wear particles stimulating the activity of bone resorbing osteoclasts. However, in this study we demonstrate for the first time that polyethylene particles stimulate another type of bone loss, mediated by the direct activity of bone mineral embedded osteocytes, termed osteocytic osteolysis or osteocyte perilacunar remodelling. This study provides new mechanistic insight into wear-particle mediated bone loss and represents a new paradigm for the way in which bone cells, namely osteocytes, the key controlling cell type in bone, react to biomaterials. © 2016 Acta Materialia Inc. Source


Crotti T.N.,University of Adelaide | Dharmapatni A.A.S.S.K.,University of Adelaide | Alias E.,University of Adelaide | Alias E.,National University of Malaysia | And 4 more authors.
Arthritis Research and Therapy | Year: 2012

Introduction: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR.Methods: ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1β over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA.Results: Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-β in cultured endothelial cells.Conclusions: Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro. © 2012 Crotti et al.; licensee BioMed Central Ltd. Source


Vandyke K.,Myeloma Research Laboratory | Vandyke K.,Center for Cancer Biology | Fitter S.,Myeloma Research Laboratory | Drew J.,Myeloma Research Laboratory | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit+ gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume. Objective: In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. Design, Patients, and Intervention: This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis. Results: Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck. Conclusions: These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck. Copyright © 2013 by The Endocrine Society. Source


Noll J.E.,Myeloma Research Laboratory | Williams S.A.,Myeloma Research Laboratory | Purton L.E.,St. Vincents Institute | Purton L.E.,University of Melbourne | And 2 more authors.
Blood Cancer Journal | Year: 2012

In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell-cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression. © 2012 Macmillan Publishers Limited All rights reserved. Source


Noll J.E.,Myeloma Research Laboratory | Noll J.E.,University of Adelaide | Williams S.A.,Myeloma Research Laboratory | Tong C.M.,Myeloma Research Laboratory | And 10 more authors.
Haematologica | Year: 2014

Multiple myeloma is an incurable hematologic cancer characterized by the clonal proliferation of malignant plasma cells within the bone marrow. Numerous studies suggest that the myeloma plasma cells occupy and alter the stromal tissue of the bone marrow as a means of enhancing their survival and growth. However, the nature and magnitude of the changes to the stromal cell tissue remain to be determined. In this study, we used mesenchymal stromal cell and osteoblast-related cell surface marker expression (STRO-1 and alkaline phosphatase, respectively) and flow cytometry to enumerate mesenchymal stromal cell and osteoblast numbers in bone marrow recovered from myeloma patients at the time of diagnosis. Using this approach, we identified an increase in the number of STRO-1 positive colony forming mesenchymal stromal cells and a concomitant decrease in alkaline phophatase osteoblasts. Notably, this increase in mesenchymal stromal cell numbers correlated closely with plasma cell burden at the time of diagnosis. In addition, in comparison with the osteoblast population, the STRO-1+ mesenchymal stromal cell population was found to express higher levels of plasma cell- and osteoclast-activating factors, including RANKL and IL-6, providing a mechanism by which an increase in mesenchymal stromal cells may promote and aid the progression of myeloma. Importantly, these findings were faithfully replicated in the C57BL/KaLwRij murine model of myeloma, suggesting that this model may present a unique and clinically relevant system in which to identify and therapeutically modulate the bone microenvironment and, in turn, alter the progression of myeloma disease. © 2013 Ferrata Storti Foundation. Source

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