Biomedical subjects

Bryan J Nestor

Publications and source records attributed to Bryan J Nestor.

9 recordsLinked to original sources

PubMed2007

The cellular and molecular biology of periprosthetic osteolysis.

The generation of prosthetic implant wear after total joint arthroplasty is recognized as the major initiating event in development of periprosthetic osteolysis and aseptic loosening, the leading complication of this otherwise successful surgical procedure. We review current concepts of how wear debris causes osteolysis, and report ideas for prevention and treatment. Wear debris primarily targets macrophages and osteoclast precursor cells, although osteoblasts, fibroblasts, and lymphocytes also may be involved. Molecular responses include activation of MAP kinase pathways, transcription factors (including NFkappaB), and suppressors of cytokine signaling. This results in up-regulation of proinflammatory signaling and inhibition of the protective actions of antiosteoclastogenic cytokines such as interferon gamma. Strategies to reduce osteolysis by choosing bearing surface materials with reduced wear properties should be balanced by awareness that reducing particle size may increase biologic activity. There are no approved treatments for osteolysis despite the promise of therapeutic agents against proinflammatory mediators (such as tumor necrosis factor) and osteoclasts (bisphosphonates and molecules blocking receptor activator of NFkappaB ligand [RANKL] signaling) shown in animal models. Considerable efforts are underway to develop such therapies, to identify novel targets for therapeutic intervention, and to develop effective outcome measures.

Animals↗

PubMed2007

Distinct inflammatory gene pathways induced by particles.

The biologic response to particulate load after arthroplasty has not been fully characterized but is believed mediated by proinflammatory cytokines released from mononuclear cells in the periprosthetic region. To investigate the contribution of lymphocytes to expression of proinflammatory genes induced by metal particles, we compared gene expression of mononuclear cells in response to metal and polymethylmethacrylate particles using cDNA microarray profiling. Peripheral blood mononuclear cells and monocytes were stimulated with polymethylmethacrylate and titanium particles of clinically relevant sizes. Polymethylmethacrylate elicited a six- to 12-fold increase in gene expression of tumor necrosis factor alpha, interleukin 1alpha, interleukin 1beta, interleukin 6, and interleukin 8 in purified monocytes and unfractionated peripheral blood mononuclear cells. Although the effect of titanium on stimulation of purified monocytes was modest, stimulation of lymphocyte-containing peripheral blood mononuclear cells by titanium particles resulted in monocyte-derived proinflammatory cytokine expression. In contrast to polymethylmethacrylate, titanium particles stimulated increased expression of T lymphocyte-derived cytokines, including interleukin 2, interferon gamma, interleukin 9, and interleukin 22, in peripheral blood mononuclear cell cultures. The induction of T cell activation by titanium particles suggests lymphocytes may contribute to the inflammation that mediates osteolysis in patients with metallic particulate debris after total joint replacement.

Cell Survival↗

PubMed2006

Involvement of complement receptor 3 (CR3) and scavenger receptor in macrophage responses to wear debris.

The ability of prosthetic wear debris to induce pro-inflammatory responses in macrophages is widely appreciated, but little is known about the molecular mechanisms involved in particle recognition. Specifically, the nature of the cell surface receptors that interact with wear debris is poorly understood. Elucidating the identities of these receptors and how they interact with different types of wear debris are critical to understanding how wear debris initiates periprosthetic osteolysis. We examined the involvement of opsonization, complement receptor 3 (CR3), and scavenger receptor A (SRA), in responses to polymethylmethacrylate (PMMA) and titanium wear particles. Serum dependence of pro-inflammatory responses to PMMA and titanium was tested, and serum proteins that adhered to these two types of particles were identified. Several serum proteins, including known opsonins such as C3bi and fibronectin, adhered to PMMA but not titanium, and serum was required for pro-inflammatory signaling induced by PMMA, but not by titanium. Phagocytosis of PMMA and titanium by macrophages was demonstrated by flow cytometry. Blocking CR3 specifically inhibited phagocytosis of PMMA by macrophages, whereas blocking SRA specifically inhibited titanium uptake. Direct involvement of CR3 and SRA in cell-particle interaction was assessed by expression of these receptors in nonphagocytic HEK293 cells. CR3 specifically induced cell binding to PMMA particles and adhesion to PMMA-coated plates, while SRA specifically induced binding to titanium particles and adhesion to titanium-coated plates. Taken together, these results suggest involvement of opsonization, complement, and integrin receptors, including CR3 and fibronectin receptors, in PMMA action, and an involvement of scavenger receptors in responses to titanium.

Fibronectins↗

PubMed2006

Influence of total hip design on dislocation: a computer model and clinical analysis.

Dislocation following hip arthroplasty remains problematic. While the etiology of dislocation may be multifactorial, implant system design may play a role. Using a computer aided design program, virtual range of motion of several commonly implanted designs was performed with prosthetic interference representing impingement used as an endpoint. Implants with small diameter head size (22 mm) and a larger trunion geometry (type II taper) demonstrated impingement in flexion at less than 90 degrees , suggesting an increased risk for dislocation. To investigate this clinically, we performed a review of a consecutive series of 254 primary hip arthroplasties performed by a single surgeon using an implant with a type II taper (Biomet, Warsaw, IN). At a minimum 2 year followup, 12 patients with 12 hips (4.8%) had at least one episode of dislocation. Stratified by head size, the dislocation rates were 3.6% for 28 mm, 4.8% for 26 mm, and 18.8% for 22 mm bearings. These findings support the notion that computer aided design modeling of implant systems is useful in evaluating range of motion and this technique could be employed during the design of any new implant system.

Arthroplasty, Replacement, Hip↗

PubMed2006

Acetabular revision with the Contour antiprotrusio cage: 2- to 5-year followup.

The Contour cage introduced in 1999 was designed to improve fixation and provide a surface for bone ongrowth. To determine whether the rates of radiographic loosening and/or revision have been reduced with the Contour design, we retrospectively reviewed the medical records and radiographs of 29 patients (average age, 68.1 years) undergoing 31 acetabular revisions with a Contour cage. The minimum followup was 24 months (mean 30 months, range, 24-58 months). Based on the Paprosky classification, two hips were Type 2B, seven were Type 3A, and 22 were Type 3B. Two hips (7%) were revised for loosening; one of these two was also infected. An additional five hips (16%) had signs of radiographic loosening. The mean Harris hip score improved from 45 to 80; functional scores improved less than the pain scores. Only 14 hips (45%) had an excellent or good clinical result and three of these 14 hips had radiographic signs of loosening; presuming these three hips eventually fail, only 35% of the hips had a good or excellent result. We found an association between number of previous surgeries and radiographic loosening and revision. Our data suggest the Contour cage offers little advantage over other antiprotrusio cages and highlight the substantial limitations of current methods available for treating patients with extensive acetabular bone loss.

Acetabulum↗

PubMed2006

Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon-gamma. Mechanistic insights and implications for periprosthetic osteolysis.

BACKGROUND: Wear debris challenge of macrophages provokes the generation of proinflammatory cytokines, which contribute to periprosthetic osteolysis. However, it is not known whether this effect is accompanied by reprogramming of other cytokines present within the periprosthetic tissue that may be involved in anti-osteoclastogenic activities. In the present study, we examined the ability of wear debris particles to inhibit the signaling of two such cytokines, interleukin-6 and interferon-gamma. METHODS: Human osteoclast precursor cells were challenged with particles of titanium or polymethylmethacrylate bone cement prior to the addition of the cytokines interleukin-6 or interferon-gamma. Interleukin-6 signaling was determined by measuring the activation of STAT3 signal transduction with use of immunoblotting and electrophoretic mobility shift assays. Interferon-gamma signaling was determined by measuring the activation of STAT1 with use of immunoblotting and electrophoretic mobility shift assays and by measuring the expression of interferon-gamma-inducible genes with use of real-time reverse transcription-polymerase chain reaction assays. Involvement of mitogen-activated protein kinases in cytokine signaling was assessed by including mitogen-activated protein kinase inhibitors in these assays and also by means of immunoblot assessment of mitogen-activated protein kinase activation by wear debris particles. Wear debris modulation of expression of the cytokine suppressors SOCS1 and SOCS3 (as well as pro-inflammatory mediators) was assessed with use of real-time reverse transcription-polymerase chain reaction assays. RESULTS: Both titanium and polymethylmethacrylate particles potently inhibited interleukin-6-induced STAT3 activation in human osteoclast precursor cells. Inhibition of p38 mitogen-activated protein kinase, which is activated by titanium and polymethylmethacrylate, reversed the inhibitory effects of these particles on interleukin-6 signaling, whereas inhibition of ERK and JNK mitogen-activated protein kinases (which are also activated by both types of wear debris) had no effect. Titanium and polymethylmethacrylate also both induced expression of SOCS3, an inhibitor of interleukin-6 signaling. In addition to its effects on interleukin-6 signaling, titanium also profoundly inhibited the interferon-gamma-induced activation of STAT1 and the expression of interferon-gamma-inducible genes, whereas polymethylmethacrylate had no effect on interferon-gamma signaling. CONCLUSIONS: Titanium inhibits both interferon-gamma and interleukin-6 signaling in human osteoclast precursor cells, whereas polymethylmethacrylate bone cement inhibits only the latter. Wear particle inhibition of interleukin-6 specifically involves the activation of p38 mitogen-activated protein kinase and is accompanied by substantial induction of SOCS3, an inhibitor of interleukin-6 signaling. In contrast, titanium inhibition of interferon-gamma signaling is not dependent on mitogen-activated protein kinase activation and is accompanied by only modest induction of the interferon-gamma inhibitor SOCS1.

Bone Cements↗

PubMed2006

Cyclooxygenase-2 inhibitors in human skeletal fracture healing.

This article identifies the underlying molecular events responsible for fracture nonunions in a subset of fracture patients. Expression profiling of fracture callus tissue from both uneventful fracture repair and nonunion outcomes showed a decrease of COX-2 expression and an inability to mount an immune response in nonunion fractures. Validation in vitro with Saos-2 osteoprogenitor cell lines showed a decrease in osteogenesis potential after the cells were treated with celecoxib, a COX-2 specific inhibitor and anti-inflammatory agent. This article recapitulates that an initial immune response is crucial to fracture healing and suggests limited usage of COX-2 inhibitors in patients with healing fractures.

Adult↗

PubMed2004

Wear of a highly cross-linked polyethylene liner associated with metallic deposition on a ceramic femoral head.

A 68-year-old patient underwent revision surgery for recurrent dislocation of a ceramic-on-polyethylene uncemented hip arthroplasty implanted 6 months previously. The aluminum oxide femoral head was found to have titanium deposition measuring 5 by 10 mm in an area articulating with the highly cross-linked polyethylene liner. The liner was observed to possess severe scratching produced by articulation with the titanium deposited on the ceramic head. Despite improved scratch resistance of ceramic-bearing surfaces, irregularities introduced by metallic deposition after recurrent dislocation can damage a highly cross-linked polyethylene liner.

Aged↗

PubMed2004

Magnetic resonance imaging after total hip arthroplasty: evaluation of periprosthetic soft tissue.

BACKGROUND: The evaluation of periprosthetic osteolysis in patients who have had a total hip arthroplasty is challenging, and traditional imaging techniques, including magnetic resonance imaging and computerized tomography, are limited by metallic artifact. The purpose of the present study was to investigate the use of modified magnetic resonance imaging techniques involving commercially available software to visualize periprosthetic soft tissues, to define the bone-implant interface, and to detect the location and extent of osteolysis. METHODS: Twenty-eight hips in twenty-seven patients were examined to assess the extent of osteolysis (nineteen hips), enigmatic pain (five), heterotopic ossification (two), suspected tumor (one), or femoral nerve palsy (one). The results were correlated with conventional radiographic findings as well as with intraoperative findings (when available). RESULTS: Magnetic resonance imaging demonstrated the bone-implant interface and the surrounding soft-tissue envelope in all hips. Radiographs consistently underestimated the extent and location of acetabular osteolysis when compared with magnetic resonance imaging. Magnetic resonance imaging also disclosed radiographically occult extraosseous soft-tissue deposits that were similar in signal intensity to areas of osteolysis, demonstrated the relationship of these deposits to adjacent neurovascular structures, and allowed further visualization of hypertrophic synovial deposits that accompanied the bone resorption in twenty-five of the twenty-eight hips. CONCLUSIONS: Magnetic resonance imaging is effective for the assessment of the periprosthetic soft tissues in patients who have had a total hip arthroplasty. While not indicated for every patient who has pain at the site of an arthroplasty, these techniques can be effective for the evaluation of the surrounding soft-tissue envelope as well as intracapsular synovial deposits and are more effective than radiographs for the detection and evaluation of osteolysis, thus aiding in clinical management.

Adult↗