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1.  Macrophages – Key Cells in the Response to Wear Debris from Joint Replacements 
The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of pro-inflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented.
PMCID: PMC3775910  PMID: 23568608
Total joint replacement; Aseptic loosening; Osteolysis; Monocyte/macrophage; Wear particles; Inflammation; Tissue homeostasis
Acta biomaterialia  2013;9(9):8046-8058.
Aseptic loosening and other wear-related complications are one of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) predates aseptic loosening in many cases indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery-, and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL due to changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality, and muscle coordination/strength. Later large numbers of wear particles detached from TKAs trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, an impairment of osteoblast function, mechanical stresses, and an increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design, and material factors are the most important preventative factors because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented with pharmacological interventions.
PMCID: PMC4003873  PMID: 23669623
total knee arthroplasty; osteolysis; aseptic loosening; wear particles; polyethylene; particle disease; joint fluid; knee biomechanics; implant alignment; patient-related factors; hypersensitivity; biomaterial solution; pharmacological interventions
3.  Particle disease: Biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty 
Innate immunity  2012;19(2):213-224.
Numerous studies provide detailed insight into the triggering and amplification mechanisms of the inflammatory response associated with prosthetic wear particles, promoting final dominance of bone resorption over bone formation in multiple bone multicellular units around an implant. In fact, inflammation is a highly regulated process tightly linked to simultaneous stimulation of tissue protective and regenerative mechanisms in order to prevent collateral damage of periprosthetic tissues. A variety of cytokines, chemokines, hormones and specific cell populations, including macrophages, dendritic and stem cells, attempt to balance tissue architecture and minimize inflammation. Based on this fact, we postulate that the local tissue homeostatic mechanisms more effectively regulate the pro-inflammatory/pro-osteolytic cells/pathways in patients with none/mild periprosthetic osteolysis (PPOL) than in patients with severe PPOL. In this line of thinking, ‘particle disease theory’ can be understood, at least partially, in terms of the failure of local tissue homeostatic mechanisms. As a result, we envision focusing current research on homeostatic mechanisms in addition to traditional efforts to elucidate details of pro-inflammatory/pro-osteolytic pathways. We believe this approach could open new avenues for research and potential therapeutic strategies.
PMCID: PMC3712274  PMID: 22751380
Homeostatic mechanisms; periprosthetic osteolysis; inflammatory response; tissue-appropriate response; osteoclasts; dendritic cells; macrophages; fibroblasts; lymphocytes; cytokines total hip arthroplasty; replacement
4.  Toll-like receptors in human chondrocytes and osteoarthritic cartilage 
Acta Orthopaedica  2013;84(6):585-592.
Background and purpose
Degenerating cartilage releases potential danger signals that react with Toll-like receptor (TLR) type danger receptors. We investigated the presence and regulation of TLR1, TLR2, and TLR9 in human chondrocytes.
We studied TLR1, TLR2, TLR4, and TLR9 mRNA (qRT-PCR) and receptor proteins (by immunostaining) in primary mature healthy chondrocytes, developing chondrocytes, and degenerated chondrocytes in osteoarthritis (OA) tissue sections of different OARSI grades. Effects of a danger signal and of a pro-inflammatory cytokine on TLRs were also studied.
In primary 2D-chondrocytes, TLR1 and TLR2 were strongly expressed. Stimulation of 2D and 3D chondrocytes with a TLR1/2-specific danger signal increased expression of TLR1 mRNA 1.3- to 1.8-fold, TLR2 mRNA 2.6- to 2.8-fold, and TNF-α mRNA 4.5- to 9-fold. On the other hand, TNF-α increased TLR1 mRNA] expression 16-fold, TLR2 mRNA expression 143- to 201-fold, and TNF-α mRNA expression 131- to 265-fold. TLR4 and TLR9 mRNA expression was not upregulated. There was a correlation between worsening of OA and increased TLR immunostaining in the superficial and middle cartilage zones, while chondrocytes assumed a CD166× progenitor phenotype. Correspondingly, TLR expression was high soon after differentiation of mesenchymal stem cells to chondrocytes. With maturation, it declined (TLR2, TLR9).
Mature chondrocytes express TLR1 and TLR2 and may react to cartilage matrix/chondrocyte-derived danger signals or degradation products. This leads to synthesis of pro-inflammatory cytokines, which stimulate further TLR and cytokine expression, establishing a vicious circle. This suggests that OA can act as an autoinflammatory disease and links the old mechanical wear-and-tear concept with modern biochemical views of OA. These findings suggest that the chondrocyte itself is the earliest and most important inflammatory cell in OA.
PMCID: PMC3851674  PMID: 24237425
5.  Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy 
Osteosarcoma (OS) is one of the most common malignant bone tumors in early adolescence. Multi-drug chemotherapy has greatly increased the five year survival rate from 20% to 70%. However, the rate has been staggering for 30 years and the prognosis is particularly poor for patients with recurrence and metastasis. Our study aimed to investigate the role of Wnt-β-catenin, Notch and Hedgehog pathway in OS development because all these pathways are involved in skeletal development, tumorigenesis and chemoresistance. Our results showed that the major components in Wnt-β-catenin pathway, e.g. Wnt3a, β-catenin and Lef1, were consistently upregulated in human osteosarcoma cell line Saos2 cells compared to human fetal osteoblasts (hFOB), whereas the changes in the expression levels of Notch and Hh signaling molecules were not consistent. Knocking down β-catenin increased the Saos2 sensitivity to methotrexate (MTX) induced cell death. Consistently, the expression level of β-catenin protein correlated with the invasiveness of OS, as evidenced by more intensive β-catenin immunoreactivity in higher grade OS samples. Chemical inhibition of the Wnt-β-catenin signaling enhanced MTX mediated death of Saos2 cells. A synergistic effect with MTX was observed when both inhibitors for Wnt-β-catenin and Notch pathways were simultaneously used, while the addition of the Hh inhibitor did not further improve the efficacy. Our findings provide some novel insight to OS pathogenesis and lay a foundation for future application of Wnt-β-catenin and Notch inhibitors together with the currently used chemotherapeutic drugs to improve the outcome of OS treatment.
PMCID: PMC3710725  PMID: 23291185
Osteosarcoma; Catenin; Notch; Pathway; Methotrexate; Apoptosis
6.  Circadian Timekeeping Is Disturbed in Rheumatoid Arthritis at Molecular Level 
PLoS ONE  2013;8(1):e54049.
Patients with rheumatoid arthritis (RA) have disturbances in the hypothalamic-pituitary-adrenal (HPA) axis. These are reflected in altered circadian rhythm of circulating serum cortisol, melatonin and IL-6 levels and in chronic fatigue. We hypothesized that the molecular machinery responsible for the circadian timekeeping is perturbed in RA. The aim of this study was to investigate the expression of circadian clock in RA.
Gene expression of thirteen clock genes was analyzed in the synovial membrane of RA and control osteoarthritis (OA) patients. BMAL1 protein was detected using immunohistochemistry. Cell autonomous clock oscillation was started in RA and OA synovial fibroblasts using serum shock. The effect of pro-inflammatory stimulus on clock gene expression in synovial fibroblasts was studied using IL-6 and TNF-α.
Gene expression analysis disclosed disconcerted circadian timekeeping and immunohistochemistry revealed strong cytoplasmic localization of BMAL1 in RA patients. Perturbed circadian timekeeping is at least in part inflammation independent and cell autonomous, because RA synovial fibroblasts display altered circadian expression of several clock components, and perturbed circadian production of IL-6 and IL-1β after clock resetting. However, inflammatory stimulus disturbs the rhythm in cultured fibroblasts. Throughout the experiments ARNTL2 and NPAS2 appeared to be the most affected clock genes in human immune-inflammatory conditions.
We conclude that the molecular machinery controlling the circadian rhythm is disturbed in RA patients.
PMCID: PMC3546002  PMID: 23335987
7.  Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis 
PLoS ONE  2012;7(1):e30275.
Background and Objectives
Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT).
A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias.
Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo.
No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.
PMCID: PMC3260264  PMID: 22272322
9.  Immune-Regulatory Mechanisms in Systemic Autoimmune and Rheumatic Diseases 
Systemic autoimmune and rheumatic diseases (SAIRDs) are thought to develop due to the failure of autoimmune regulation and tolerance. Current therapies, such as biologics, have improved the clinical results of SAIRDs; however, they are not curative treatments. Recently, new discoveries have been made in immune tolerance and inflammation, such as tolerogenic dendritic cells, regulatory T and B cells, Th 17 cells, inflammatory and tolerogenic cytokines, and intracellular signaling pathways. They lay the foundation for the next generation of the therapies beyond the currently used biologic therapies. New drugs should target the core processes involved in disease mechanisms with the aim to attain complete cure combined with safety and low costs compared to the biologic agents. Re-establishment of autoimmune regulation and tolerance in SAIRDs by the end of the current decade should be the final and realistic target.
PMCID: PMC3207139  PMID: 22110541
10.  Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing 
PLoS ONE  2011;6(2):e16947.
Fracture healing is orchestrated by a specific set of events that culminates in the repair of bone and reachievement of its biomechanical properties. The aim of our work was to study the sequence of gene expression events involved in inflammation and bone remodeling occurring in the early phases of callus formation in osteoporotic patients.
Methodology/Principal Findings
Fifty-six patients submitted to hip replacement surgery after a low-energy hip fracture were enrolled in this study. The patients were grouped according to the time interval between fracture and surgery: bone collected within 3 days after fracture (n = 13); between the 4th and 7th day (n = 33); and after one week from the fracture (n = 10). Inflammation- and bone metabolism-related genes were assessed at the fracture site. The expression of pro-inflammatory cytokines was increased in the first days after fracture. The genes responsible for bone formation and resorption were upregulated one week after fracture. The increase in RANKL expression occurred just before that, between the 4th–7th days after fracture. Sclerostin expression diminished during the first days after fracture.
The expression of inflammation-related genes, especially IL-6, is highest at the very first days after fracture but from day 4 onwards there is a shift towards bone remodeling genes, suggesting that the inflammatory phase triggers bone healing. We propose that an initial inflammatory stimulus and a decrease in sclerostin-related effects are the key components in fracture healing. In osteoporotic patients, cellular machinery seems to adequately react to the inflammatory stimulus, therefore local promotion of these events might constitute a promising medical intervention to accelerate fracture healing.
PMCID: PMC3037947  PMID: 21347301
11.  Prevention of deep infection in joint replacement surgery 
Acta Orthopaedica  2010;81(6):660-666.
PMCID: PMC3216074  PMID: 21110700
12.  Younger age increases the risk of early prosthesis failure following primary total knee replacement for osteoarthritis 
Acta Orthopaedica  2010;81(4):413-419.
Background and purpose
Total knee replacements (TKRs) are being increasingly performed in patients aged ≤ 65 years who often have high physical demands. We investigated the relation between age of the patient and prosthesis survival following primary TKR using nationwide data collected from the Finnish Arthroplasty Register.
From Jan 1, 1997 through Dec 31, 2003, 32,019 TKRs for primary or secondary osteoarthritis were reported to the Finnish Arthroplasty Register. The TKRs were followed until the end of 2004. During the follow-up, 909 TKRs were revised, 205 (23%) due to infection and 704 for other reasons.
Crude overall implant survival improved with increasing age between the ages of 40 and 80. The 5-year survival rates were 92% and 95% in patients aged ≤ 55 and 56–65 years, respectively, compared to 97% in patients who were > 65 years of age (p < 0.001). The difference was mainly attributable to reasons other than infections. Sex, diagnosis, type of TKR (condylar, constrained, or hinge), use of patellar component, and fixation method were also associated with higher revision rates. However, the differences in prosthesis survival between the age groups ≤ 55, 56–65, and > 65 years remained after adjustment for these factors (p < 0.001).
Young age impairs the prognosis of TKR and is associated with increased revision rates for non-infectious reasons. Diagnosis, sex, type of TKR, use of patellar component, and fixation method partly explain the differences, but the effects of physical activity, patient demands, and obesity on implant survival in younger patients warrant further research.
PMCID: PMC2917562  PMID: 20809740
13.  BMPs in periprosthetic tissues around aseptically loosened total hip implants 
Acta Orthopaedica  2010;81(4):420-426.
Background and purpose
Primary and dynamically maintained periprosthetic bone formation is essential for osseointegration of hip implants to host bone. Bone morphogenetic proteins (BMPs) play a role in osteoinductive bone formation. We hypothesized that there is an increased local synthesis of BMPs in the synovial membrane-like interface around aseptically loosened total hip replacement (THR) implants, as body attempts to generate or maintain implant fixation.
Patients and methods
We compared synovial membrane-like interface tissue from revised total hip replacements (rTHR, n = 9) to osteoarthritic control synovial membrane samples (OA, n = 11. Avidin-biotin-peroxidase complex staining and grading of BMP-2, BMP-4, BMP-6, and BMP-7 was done. Immunofluorescence staining was used to study BMP proteins produced by mesenchymal stromal/stem cells (MSCs) and osteoblasts.
Results and interpretation
All BMPs studied were present in the synovial lining or lining-like layer, fibroblast-like stromal cells, interstitial macrophage-like cells, and endothelial cells. In OA and rTHR samples, BMP-6 positivity in cells, inducible by the proinflammatory cytokines tumor necrosis factor−α and interleukin-1β, predominated over expression of other BMPs. Macrophage-like cells positive for BMP-4, inducible in macrophages by stimulation with particles, were more frequent around loosened implants than in control OA samples, but apparently not enough to prevent loosening. MSCs contained BMP-2, BMP-4, BMP-6, and BMP-7, but this staining diminished during osteogenesis, suggesting that BMPs are produced by progenitor cells in particular, probably for storage in the bone matrix.
PMCID: PMC2917563  PMID: 20515435
14.  Whole-mount specimens in the analysis of en bloc samples obtained from revisions of resurfacing hip implants 
Acta Orthopaedica  2010;81(3):324-330.
Modern metal-on-metal hip resurfacing implants are being increasingly used for young and active patients, although the long-term outcome and failure mechanisms of these implants are still unknown. In this consecutive revision case series, early failures of femoral implants (at < 4 years) were studied.
3 revisions were done due to a fracture of the femoral neck and 1 due to loosening and varus position of the femoral component. Femoral heads were removed en bloc 2–46 months after the primary operation, embedded in methylmethacrylate, sectioned, stained, and analyzed as whole-mount specimens in 4 55–62-year-old patients with osteoarthritis.
Histopathology was characterized by new but also partly healed trabecular microfractures, bone demineralization, cysts, metallosis, and abnormal formation of new woven bone. All samples displayed signs of notching, osteoporosis, and aseptic necrosis, which seemed to have been the main reason for the subsequent development and symptoms of the patients and revision operations of the hips.
Based on these early revision cases, it appears that aseptic necrosis is a common cause of early loosening of resurfacing hip implants.
PMCID: PMC2876834  PMID: 20367416
15.  Chronic arthritis leads to disturbances in the bone collagen network 
In this study we used a mice model of chronic arthritis to evaluate if bone fragility induced by chronic inflammation is associated with an imbalance in bone turnover and also a disorganization of the bone type I collagen network.
Serum, vertebrae and femur bones were collected from eight-month-old polyarthritis SKG mice and controls. Strength of the femoral bones was evaluated using three-point bending tests and density was assessed with a pycnometer. Bone turnover markers carboxy-terminal collagen cross-linking telopeptides (CTX-I) and amino-terminal propeptide of type I procollagen (PINP) were measured in serum. The organization and density of bone collagen were analyzed in vertebrae using second-harmonic generation (SHG) imaging with a two-photon microscope and trabecular bone microstructure was assessed by scanning electron microscope (SEM).
Femoral bones of SKG mice revealed increased fragility expressed by deterioration of mechanical properties, namely altered stiffness (P = 0.007) and reduced strength (P = 0.006), when compared to controls. Accordingly, inter-trabecular distance and trabecular thickness as observed by SEM were reduced in SKG mice. PINP was significantly higher in arthritic mice (9.18 ± 3.21 ng/ml) when compared to controls (1.71 ± 0.53 ng/ml, P < 0.001). Bone resorption marker CTX-I was 9.67 ± 3.18 ng/ml in arthritic SKG mice compared to 6.23 ± 4.11 ng/ml in controls (P = 0.176). The forward-to-backward signal ratio measured by SHG was higher in SKG animals, reflecting disorganized matrix and loose collagen structure, compared to controls.
We have shown for the first time that chronic arthritis by itself impairs bone matrix architecture, probably due to disturbed bone remodeling and increased collagen turnover. This effect might predispose patients to bone fragility fractures.
PMCID: PMC2875635  PMID: 20078856
16.  Persisting High Levels of Synovial Fluid Markers after Cartilage Repair 
Local attempts to repair a cartilage lesion could cause increased levels of anabolic and catabolic factors in the synovial fluid. After repair with regenerated cartilage, the homeostasis of the cartilage ideally would return to normal. In this pilot study, we first hypothesized levels of synovial fluid markers would be higher in patients with cartilage lesions than in patients with no cartilage lesions, and then we hypothesized the levels of synovial fluid markers would decrease after cartilage repair. We collected synovial fluid samples from 10 patients before autologous chondrocyte transplantation of the knee. One year later, a second set of samples was collected and arthroscopic evaluation of the repair site was performed. Fifteen patients undergoing knee arthroscopy for various symptoms but with no apparent cartilage lesions served as control subjects. We measured synovial fluid matrix metalloproteinase-3 (MMP-3) and insulinlike growth factor-I (IGF-I) concentrations with specific activity and enzyme-linked immunosorbent assays, respectively. The levels of MMP-3 and IGF-I were higher in patients having cartilage lesions than in control subjects with no cartilage lesions. One year after cartilage repair, the lesions were filled with repair tissue, but the levels of MMP-3 and IGF-I remained elevated, indicating either graft remodeling or early degeneration.
Level of Evidence: Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC2601000  PMID: 18709427
17.  Low rate of infected knee replacements in a nationwide series—is it an underestimate? 
Acta Orthopaedica  2009;80(2):205-212.
Background and purpose Specialist hospitals have reported an incidence of early deep infections of < 1% following primary knee replacement. The purpose of this study was to estimate the infection rate in a nationwide series using register-based data.
Methods The Finnish Arthroplasty Register (FAR) was searched for primary unicompartmental, total, and revision knee arthroplasties performed in 1997 through 2003 and eventual revision arthroplasties. The FAR data on revision arthroplasties was supplemented by a search of the national Hospital Discharge Register (HDR) for debridements, partial and total revision knee replacements, resection arthroplasties, arthrodeses, and amputations.
Results During the first postoperative year, 0.33% (95% CI: 0.13–0.84), 0.52% (0.45–0.60) and 1.91% (1.40–2.61) of the primary UKAs, primary TKAs, and revision TKAs, respectively, were reoperated due to infection. The 1-year rate of reoperations due to infection remained constant in all arthroplasty groups over the observation period.
The overall infection rate calculated using FAR data only was 0.77% (95% CI: 0.69–0.86), which was lower, but was not, however, statistically significantly different from the overall infection rate calculated using endpoint data combined from FAR and HDR records (0.89%; 95% CI: 0.80–0.99). FAR registered revision arthroplasties and patellar resurfacing arthroplasties reliably but missed a considerable proportion of other reoperations.
Interpretation More reoperations performed due to infection can be expected as the numbers of knee arthroplasties increase, since there has been no improvement in the early infection rate. Finnish Arthroplasty Register data appear to underestimate the incidence of reoperations performed due to infection.
PMCID: PMC2823163  PMID: 19404805
18.  Human parainfluenza virus type 2 (HPIV2) induced host ADAM8 expression in human salivary adenocarcinoma cell line (HSY) during cell fusion 
BMC Microbiology  2009;9:55.
The aim of the study was to investigate expression of ADAMs (A Disintegrin and A Metalloproteinase) of host cell origin during cell-cell fusion induced by human parainfluenza virus type 2 (HPIV2).
Induction of host cell ADAM9 was observed in GMK cells, but the applicability of this model was restricted by lack of cross-reactivity of the anti-human ADAM8 antibodies with the corresponding green monkey antigens. HSG cells were not susceptible to HPIV2 virus infection. In contrast, in human parotid gland HSY cells, a natural host cell for paramyxoviruses, HPIV2 induced ADAM8 expression. ADAM8 staining increased dramatically over time from 7.9 ± 3% at zero hours to 99.2 ± 0.8% at 72 hours (p = 0.0001). Without HPIV2 the corresponding percentages were only 7.7% and 8.8%. Moreover, ADAM8 positive cells formed bi- (16.2%) and multinuclear cells (3.5%) on day one and the corresponding percentages on day three were 15.6% for binuclear and 57.2% for multinuclear cells.
ADAM8, well recognized for participation in cell-to-cell fusion especially in osteoclast formation, is up-regulated upon formation of multinuclear giant cells after HPIV2 induction in HSY cells. The virus-HSY cell system provides a novel experimental model for study of the molecular mechanism of cell fusion events.
PMCID: PMC2662866  PMID: 19284887
19.  Outcome of prosthesis exchange for infected knee arthroplasty: the effect of treatment approach 
Acta Orthopaedica  2009;80(1):67-77.
Background and purpose Two-stage revision remains the gold standard in the treatment of infected knee arthroplasty. Lately, good long-term results of direct exchange arthroplasty have been reported. The purpose of this literature review is to compare the clinical outcome achieved with one-stage revision and two-stage revision with different types of spacers.
Methods A thorough systematic review of literature was undertaken to idenepsy reports on the treatment alternatives. Papers written in English or including an English abstract, published from 1980 through 2005, and reporting either the success rate in eradication of infection or the clinical status achieved were reviewed. 31 original articles describing the results of 154 one-stage exchange arthoplasties and of 926 two-stage exchange arthoplasties were included. The depth of detail in the description of materials and methods varied markedly, making it impossible to perform a meta-analysis. Instead, a descriptive review of the results is presented.
Results With a follow-up of 12–122 months, the overall success rate in eradication of infection was 73–100% after one-stage revisions and 82–100% after two-stage revisions. Reinfection rates were the lowest in series where articulating cement spacers were used, though the follow-up was relatively short. Studies using articulating spacers reported the highest average postoperative ranges of motion. Otherwise, no correlations were observed between the clinical outcome and the length of follow-up, the type of revision, or the type of spacer. The clinical outcome (knee scores and range of motion) of the one-stage revisions was no different from that of the two-stage revisions.
Interpretation Two-stage exchange is an effective treatment. Mobile spacers may further improve the range of motion. More experience in one-stage revision is required in order to define its role in the management of infected knee arthroplasties.
PMCID: PMC2823239  PMID: 19234888
20.  Load-Bearing Biomedical Applications of Diamond-Like Carbon Coatings - Current Status 
The current status of diamond-like carbon (DLC) coatings for biomedical applications is reviewed with emphasis on load-bearing coatings. Although diamond-like carbon coating materials have been studied for decades, no indisputably successful commercial biomedical applications for high load situations exist today. High internal stress, leading to insufficient adhesion of thick coatings, is the evident reason behind this delay of the break-through of DLC coatings for applications. Excellent adhesion of thick DLC coatings is of utmost importance for load-bearing applications. According to this review superior candidate material for articulating implants is thick and adherent DLC on both sliding surfaces. With the filtered pulsed arc discharge method, all the necessary requirements for the deposition of thick and adherent DLC are fulfilled, provided that the substrate material is selected properly.
PMCID: PMC2687109  PMID: 19478929
Diamond-like carbon; biomedical applications; load-bearing coatings.
21.  The effect of geometry and abduction angle on the stresses in cemented UHMWPE acetabular cups – finite element simulations and experimental tests 
Contact pressure of UHMWPE acetabular cup has been shown to correlate with wear in total hip replacement (THR). The aim of the present study was to test the hypotheses that the cup geometry, abduction angle, thickness and clearance can modify the stresses in cemented polyethylene cups.
Acetabular cups with different geometries (Link®: IP and Lubinus eccentric) were tested cyclically in a simulator at 45° and 60° abduction angles. Finite element (FE) meshes were generated and two additional designs were reconstructed to test the effects of the cup clearance and thickness. Contact pressures at cup-head and cup-cement interfaces were calculated as a function of loading force at 45°, 60° and 80° abduction angles.
At the cup-head interface, IP experienced lower contact pressures than the Lubinus eccentric at low loading forces. However, at higher loading forces, much higher contact pressures were produced on the surface of IP cup. An increase in the abduction angle increased contact pressure in the IP model, but this did not occur to any major extent with the Lubinus eccentric model. At the cup-cement interface, IP experienced lower contact pressures. Increased clearance between cup and head increased contact pressure both at cup-head and cup-cement interfaces, whereas a decreased thickness of polyethylene layer increased contact pressure only at the cup-cement interface. FE results were consistent with experimental tests and acetabular cup deformations.
FE analyses showed that geometrical design, thickness and abduction angle of the acetabular cup, as well as the clearance between the cup and head do change significantly the mechanical stresses experienced by a cemented UHMWPE acetabular cup. These factors should be taken into account in future development of THR prostheses. FE technique is a useful tool with which to address these issues.
PMCID: PMC1173123  PMID: 15904521
22.  DAP12/TREM2 Deficiency Results in Impaired Osteoclast Differentiation and Osteoporotic Features 
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), Nasu-Hakola disease, is a globally distributed recessively inherited disease. PLOSL is characterized by cystic bone lesions, osteoporotic features, and loss of white matter in the brain leading to spontaneous bone fractures and profound presenile dementia. We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2. DAP12 is a transmembrane adaptor protein that associates with the cell surface receptor TREM2. The DAP12–TREM2 complex is involved in the maturation of dendritic cells. To test a hypothesis that osteoclasts would be the cell type responsible for the bone pathogenesis in PLOSL, we analyzed the differentiation of peripheral blood mononuclear cells isolated from DAP12- and TREM2-deficient PLOSL patients into osteoclasts. Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro. These results indicate an important role for DAP12–TREM2 signaling complex in the differentiation and function of osteoclasts.
PMCID: PMC2194176  PMID: 12925681
bone diseases; central nervous system diseases; osteoporosis; monocytes; dementia
23.  Fibroblast biology: Signals targeting the synovial fibroblast in arthritis 
Arthritis Research  2000;2(5):348-355.
Fibroblast-like cells in the synovial lining (type B lining cells), stroma and pannus tissue are targeted by many signals, such as the following: ligands binding to cell surface receptors; lipid soluble, small molecular weight mediators (eg nitric oxide [NO], prostaglandins, carbon monoxide); extracellular matrix (ECM)-cell interactions; and direct cell-cell contacts, including gap junctional intercellular communication. Joints are subjected to cyclic mechanical loading and shear forces. Adherence and mechanical forces affect fibroblasts via the ECM (including the hyaluronan fluid phase matrix) and the pericellular matrix (eg extracellular matrix metalloproteinase inducer [EMMPRIN]) matrices, thus modulating fibroblast migration, adherence, proliferation, programmed cell death (including anoikis), synthesis or degradation of ECM, and production of various cytokines and other mediators [1]. Aggressive, transformed or transfected mesenchymal cells containing proto-oncogenes can act in the absence of lymphocytes, but whether these cells represent regressed fibroblasts, chondrocytes or bone marrow stem cells is unclear.
PMCID: PMC130135  PMID: 11094447
fibroblast; rheumatoid arthritis; synovial membrane

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