Wearable sensor-based measures of step-up transfers are supplementary to patient-reported outcome measures following total joint arthroplasty.

PURPOSE: This study investigated the longitudinal assessment of step-up performance in patients undergoing total joint arthroplasty (TJA) and correlation with subjective patient reported outcome measures (PROMs). METHODS: In this sub-analysis of the ADAPT study, PROMs were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Block step-up (BS) transfers were assessed by wearable-derived measures of time. 76 patients undergoing TJA were included. Subgroups were formed isolating the worst performing quartile (low functioning (LF)) from the high functioning (HF), and outcomes were compared. RESULTS: One-year post-surgery, WOMAC function demonstrated strong correlations to WOMAC pain (Pearson's r = 0.67-0.84) and moderate correlations to BS performance (Pearson's r = 0.31-0.54). Both WOMAC and BS significantly improved with a larger effect size for the HF subgroup (0.62 vs. 0.43; p < 0.05). Patients designated to the LF subgroup at 3 months had increased odds of representing the LF subgroup at 12 months (WOMAC = 19; BS = 4). WOMAC defined 18 LF patients at 12 months follow-up. BS performance identified 9 additional LF patients. CONCLUSIONS: WOMAC function scores seem pain dominated. Measures of BS performance allow assessment of otherwise hidden residual functional impairment. Lower functioning 3 months post-surgery is predictive of longer-term impairment.

Severe hip or knee osteoarthritis is a disabling condition which not only impacts patients' mobility but restricts quality of life due to constant pain and consequential lifestyle changes.Total joint arthroplasty (TJA) has developed into a successful intervention for patients with advanced hip or knee osteoarthritis.Some patients are dissatisfied after TJA due to residual functional impairment and the inclusion of performance-based tests in the post-operative evaluation and rehabilitation allows for the assessment of otherwise hidden residual impairment.Early detection of functional impairment using the repeated block step-up (BS) transfers allows to facilitate more targeted rehabilitation for better functional outcomes.

Projections for primary hip and knee replacement surgery up to the year 2060: an analysis based on data from The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

INTRODUCTION: We estimated the number of primary total hip and knee replacements (THR and TKR) that will need to be performed up to the year 2060. METHODS: We used data from The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man on the volume of primary THRs (n=94,936) and TKRs (n=100,547) performed in 2018. We projected future numbers of THR and TKR using a static estimated rate from 2018 applied to population growth forecast data from the UK Office for National Statistics up to 2060. RESULTS: By 2060, THR and TKR volume would increase from 2018 levels by an estimated 37.7% (n=130,766) and 36.6% (n=137,341), respectively. For both males and females demand for surgery was also higher for patients aged 70 and over, with older patients having the biggest relative increase in volume over time: 70-79 years (44.6% males, 41.2% females); 80-89 years (112.4% males, 85.6% females); 90 years and older (348.0% males, 198.2% females). CONCLUSION: By 2060 demand for hip and knee joint replacement is estimated to increase by almost 40%. Demand will be greatest in older patients (70+ years), which will have significant implications for the health service requiring forward planning given that morbidity and resource use is higher in this population. These issues, coupled with two waves of COVID-19, will impact the ability of health services to deliver timely joint replacement to many patients for a number of years, requiring urgent planning.

A single dose of anti-IL-1ß antibodies prevents Western diet-induced immune activation during early stage collagenase-induced osteoarthritis, but does not ameliorate end-stage pathology.

OBJECTIVE: Metabolic dysfunction can cause IL-1ß mediated activation of the innate immune system, which could have important implications for the therapeutic efficacy of IL-1ß neutralizing drugs as treatment for OA in the context of metabolic syndrome (MetS). In the present study, we investigated whether early treatment with a single dose of IL-1ß blocking antibodies could prevent Western diet (WD) induced changes to systemic monocyte populations and their cytokine secretion profile and herewith modulate collagenase induced osteoarthritis (CiOA) pathology. METHODS: CiOA was induced in female C57Bl/6 mice fed either a standard diet (SD) or WD and treated with a single dose of either polyclonal anti-IL-1ß antibodies or control. Monocyte subsets and granulocytes in bone marrow and blood were analyzed with flow cytometry, and cytokine expression by bone marrow cells was analyzed using qPCR. Synovial cellularity, cartilage damage and osteophyte formation were assessed on histology. RESULTS: WD feeding of C57Bl/6 mice led to increased serum levels of low-density lipoprotein (LDL) and innate immune activation in the form of an increased number of Ly6Chigh cells in bone marrow and blood and increased cytokine expression of IL-6 and TNF-α by bone marrow cells. The increase in monocyte number and activity was ameliorated by anti-IL-1ß treatment. However, anti-IL-1ß treatment did not significantly affect synovial lining thickness, cartilage damage and ectopic bone formation during WD feeding. CONCLUSIONS: Single-dose systemic anti-IL-1ß treatment prevented WD-induced innate immune activation during early stage CiOA in C57Bl/6 mice, but did not ameliorate joint pathology.

The spectrum of skin-related conditions in primary care during 2015-2019-A Finnish nationwide database study.

Background: Skin-related conditions are the frequent cause of doctors' consultations in primary care. Methods: Based on nationwide data bank information of the Finnish Institute for Health and Welfare, we analysed the 20 most frequent main diagnoses for each ICD-10 category of all general practitioners' visits in the public health care in Finland over the years 2015-2019. Results: The total amount of doctor's visits was 19 204 613 of which 1 489 228 consultations (7.80%) had a skin-related condition as the main diagnosis. The most frequent skin-related conditions were eczematous eruptions, bacterial skin infections and benign skin neoplasms accounting for 749 351 consultations (50.32%). The spectrum of skin-related conditions was diverse, with a large quantity of rarer diagnoses. Some diagnoses showed significant proportional changes. Conclusions: The results demonstrate that a limited amount of conditions comprises most of the skin-related consultations in primary care in Finland. Undergraduate education in dermatology should concentrate on the most frequent conditions seen by general practitioners, but also address the wide range of skin problems.

High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive, high-grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low- and moderate-grade NETs that express somatostatin receptors (SSTRs). OBJECTIVES: To assess SSTR expression and the efficacy of SSAs in mMCC, a high-grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression-free survival (PFS) of ≥ 120 days after initiation of SSA. RESULTS: Thirty-three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response-evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152-358). Twelve of 19 patients did not have a response-evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143-1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. CONCLUSIONS: In contrast to other high-grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side-effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC.

High LDL levels lessen bone destruction during antigen-induced arthritis by inhibiting osteoclast formation and function.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and bone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated with metabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis. In this study, we induced antigen-induced arthritis (AIA) in Apoe-/- mice, which spontaneously develop high LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bone destruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe-/- mice, induction of AIA resulted in a significant reduction of bone destruction in Apoe-/- mice as compared to WT controls. In line with that, the TRAP+ area on the cortical bone was significantly decreased. The absence of Apoe did affect neither the numbers of CD11b+Ly6Chigh and CD11b-/Ly6Chigh osteoclast precursors (OCPs) in the BM of naïve mice nor their in vitro osteoclastogenic potential as indicated by comparable mRNA expression of osteoclast markers. Addition of oxLDL, but not LDL, to pre-osteoclasts from day 3 and mature osteoclasts from day 6 of osteoclastogenesis strongly reduced the number of TRAP+ osteoclasts and their resorptive capacity. This coincided with a decreased expression of various osteoclast markers. Interestingly, oxLDL significantly lowered the expression of osteoclast-associated receptor (Oscar) and the DNAX adaptor protein-12 encoding gene Tyrobp, which regulate the immunoreceptor tyrosine-based activation motif (ITAM) co-stimulation pathway that is strongly involved in osteoclastogenesis. Collectively, our findings suggest that under inflammatory conditions in the joint, high LDL levels lessen bone destruction during AIA, probably by formation of oxLDL that inhibits osteoclast formation and activity through modulation of the ITAM-signaling.

[Creation, implementation and objectives of CARADERM, a national network for rare skin carcinomas - Adnexal neoplasm part]. / Développement, mise en œuvre et objectifs de CARADERM, réseau national cancers cutanés rares ­ partie carcinomes annexiels.

INTRODUCTION: CARADERM is a French national network that includes patients with rare skin adnexal neoplasms. The present paper describes only the adnexal neoplasm part of this network. The primary objective of CARADERM is to improve medical care for malignant skin adnexal neoplasms. A multidisciplinary review group and a centralized pathological review group have been set up. PATIENTS AND METHODS: A dual network of clinicians and pathologists has been set up. Data are recorded in a secure database. RESULTS: The CARADERM network comprises of 38 clinical centres and 22 pathology centres. Between 2014 and 2017, 1598 patients with an adnexal neoplasm were included. Data of interest were documented in 80% of cases. Median patient age was 72 years. Major histological subtypes were sweat gland carcinomas (50%), hair follicle carcinomas (37.7%), and sebaceous gland carcinomas (9.8%). Surgery was the first-line treatment for 81% of patients, including 76.9% with standard surgical margin analysis, and 5.5% with exhaustive margin analysis. 920 patients (57.6%) underwent a national pathology review process. DISCUSSION: The CARADERM network aims at providing assistance in difficult situations concerning diagnosis and care in skin adnexal neoplasms. Analysis of the CARADERM data should allow the creation of a prognostic classification of these rare neoplasms together with recommendations. A national multidisciplinary consensus exists. Translational and therapeutic research is ongoing. CONCLUSION: The CARADERM network is currently recruiting and more data should lead to improved knowledge of these tumours in the coming years.

Exploring longitudinal associations of histologically assessed inflammation with symptoms and radiographic damage in knee osteoarthritis: combined results of three prospective cohort studies.

OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment.

Systematic review of the safety and efficacy of osseointegration prosthesis after limb amputation.

BACKGROUND: Osseointegration, an approach for direct skeletal attachment of a prosthesis to an amputated limb, may address many of the problems associated with socket prostheses. The safety of osseointegration remains uncertain. The aim of this study was to summarize evidence on functional and clinical outcomes, as well as adverse effects of osseointegration for patients with a limb amputation. METHODS: MEDLINE, Embase, Web of Science and the Cochrane Library were searched to April 2018. Eligible studies were observational, case and qualitative studies, and RCTs conducted in patients with a limb amputation, who were managed with osseointegrated prostheses and had follow-up data. RESULTS: Twenty-two eligible articles comprising 13 unique studies were included. No RCT was identified. Apart from three case reports that comprised one to five patients, the sample size of studies ranged from 11 to 100 participants. All relevant studies reported improvement in functional outcomes (walking ability, prosthetic use and mobility), satisfaction and quality of life following osseointegration, compared with their preoperative status or when using a conventional socket prosthesis. Infection rates ranged from 1 (95 per cent c.i. 0 to 5) to 77 (59 to 88) per cent. The majority of infections were described as low-grade soft tissue or superficial infections related to the skin-implant interface, and were treated effectively with antibiotics. None of the studies reported additional amputation or death as a result of osseointegration. CONCLUSION: Osseointegration after limb amputation improves prosthetic use, comfort when sitting, walking ability, mobility, gait and quality of life. However, it is associated with an increased risk of soft tissue infection.

The role of NOX2-derived reactive oxygen species in collagenase-induced osteoarthritis.

OBJECTIVE: Synovitis in collagenase-induced osteoarthritis (CiOA) is driven by locally released S100A8/A9 proteins and enhances joint destruction. S100A8/A9 can induce reactive oxygen species (ROS) release by phagocytes in OA synovium via neutrophil cytosolic factor-1 (Ncf1)-regulated NOX2 activation. In the present study we investigated whether NOX2-derived ROS affect joint pathology during CiOA. METHODS: CiOA was induced in knee joints of wild type (WT) and Ncf1-deficient (Ncf1**) mice. Synovial gene expression of NOX2-subunits was measured with quantitative real-time polymerase chain reaction (qRT-PCR). Joint pathology was assessed using histology and immunohistochemistry for aggrecan neo-epitope VDIPEN. Levels of inflammatory proteins were measured with Luminex or ELISA. Phagocytes in synovium, blood, bone marrow (BM) and spleen were analyzed with flow cytometry. ROS release by phagocytes was measured with a ROS detection kit. RESULTS: CiOA induction in knee joints of WT mice caused significantly increased synovial gene expression of NOX2 subunits. On day 7 of CiOA, cartilage damage and MMP activity, as measured by VDIPEN, were comparable between WT and Ncf1** mice. Synovial thickening, synovial S100A8/A9 levels and percentages of synovial macrophages, polymorphonuclear cells (PMNs), and monocytes were not different, as were levels of inflammatory mediators in serum and phagocyte percentages in blood, BM and spleen. On day 42 of CiOA, synovitis, cartilage damage, and osteophyte formation in Ncf1** mice were unaltered when compared to WT mice. ROS detection confirmed that Ncf1** PMNs lack functional NOX2, but in vitro macrophages showed ROS production, suggesting activation of compensatory mechanisms. CONCLUSIONS: Absence of Ncf1-mediated ROS production does not alter joint pathology in CiOA.

Using home sensing technology to assess outcome and recovery after hip and knee replacement in the UK: the HEmiSPHERE study protocol.

INTRODUCTION: Over 160 000 people with severe hip or knee pain caused by osteoarthritis undergo total hip (THR) or knee replacement (TKR) surgery each year in the UK within the National Health Service (NHS), and this number is expected to increase. Innovative approaches to evaluating surgical outcomes will be needed to respond to the increasing burden of joint replacement surgery. The Sensor Platform for Healthcare in a Residential Environment, Interdisciplinary Research Collaboration (SPHERE-IRC) have developed a system of sensors that can monitor the health-related behaviours of people living at home. The system includes sensors for the home environment (measuring temperature, humidity, room occupancy, water and electricity usage), a wristband body-worn activity monitor and silhouette (body outline) sensors. The aim of HEmiSPHERE (Hip and knEe study of a Sensor Platform of HEalthcare in a Residential Environment) is to (1) determine the accuracy and feasibility of the sensory data as it compares with conventional assessment of health outcomes after surgery using patient self-reported questionnaires, and (2) to explore how the SPHERE system is useful for everyday clinical decision-making. METHODS AND ANALYSIS: A feasibility study recruiting and installing the SPHERE system in the homes of up to 30 NHS adult patients as they undergo a THR or TKR. Through a mixed-methods design, the SPHERE system will monitor and record continuous measurements of daily behaviour. Main outcomes will assess the relationships between environmental, behavioural and movement data and the parameters of interest from the standard clinical assessments measuring patient outcomes over time. Patient interviews and focus groups with consultant orthopaedic surgeons will provide in-depth understanding of the acceptability, feasibility and accuracy of the data. ETHICS AND DISSEMINATION: We aim to disseminate the findings through regional talks and seminars, international conferences and peer-reviewed journals and social media.

Is the rate of revision of 36 mm metal-on-metal total hip arthroplasties with Pinnacle acetabular components related to the year of the initial operation? an interrupted time-series analysis using data from the National Joint Registry for England and Wales.

AIMS: The aim of this study was to determine whether the rates of revision for metal-on-metal (MoM) total hip arthroplasties (THAs) with Pinnacle components varied according to the year of the initial operation, and compare these with the rates of revision for other designs of MoM THA. PATIENTS AND METHODS: Data from the National Joint Registry for England and Wales included 36 mm MoM THAs with Pinnacle acetabular components which were undertaken between 2003 and 2012 with follow-up for at least five years (n = 10 776) and a control group of other MoM THAs (n = 13 817). The effect of the year of the primary operation on all-cause rates of revision was assessed using Cox regression and interrupted time-series analysis. RESULTS: For MoM THAs involving Pinnacle components, those undertaken between 2007 and 2012 had higher rates of revision compared with those undertaken between 2004 and 2006 (hazard ratio (HR) 2.01; 95% confidence interval (CI) 1.57 to 2.57; p < 0.001). For THAs undertaken during and after 2007, the number of revisions per 1000 implant-years at risk significantly increased by 5.20 (95% CI 0.52 to 9.89; p = 0.033) compared with those undertaken before this time. In the control group, THAs undertaken between 2007 and 2012 also had higher rates of revision (HR 1.77; 95% CI 1.49 to 2.10; p < 0.001), with revisions per 1000 implant-years for those undertaken during and after 2007 significantly increasing by 6.13 (95% CI 1.42 to 10.83; p = 0.016). CONCLUSION: The five-year revision rates were significantly increased for all primary MoM THAs undertaken from 2007 onwards. Contrary to recent reports, this finding was not specific to those involving Pinnacle acetabular components and may be explained by increased surveillance and recent lowering of the threshold for revision. Cite this article: Bone Joint J 2018;100-B:33-41.

An analysis of 30-day mortality after weekend versus weekday elective joint arthroplasty in England and Wales: a cohort study using the National Joint Registry Dataset.

AIMS: To investigate whether elective joint arthroplasty performed at the weekend is associated with a different 30-day mortality versus that performed between Monday and Friday. PATIENTS AND METHODS: We examined the 30-day cumulative mortality rate (Kaplan-Meier) for all elective hip and knee arthroplasties performed in England and Wales between 1st April 2003 and 31st December 2014, comprising 118 096 episodes undertaken at the weekend and 1 233 882 episodes performed on a weekday. We used Cox proportional-hazards regression models to assess for time-dependent variation and adjusted for identified risk factors for mortality. RESULTS: The cumulative 30-day mortality for hip arthroplasty was 0.15% (95% confidence interval (CI) 0.12 to 0.19) for patients operated on at the weekend versus 0.20% (95% CI 0.19 to 0.21) for patients undergoing surgery during the normal working week. For knee arthroplasty, the cumulative 30-day mortality was 0.14% (95% CI 0.11 to 0.17) for weekend-operated patients versus 0.18% (95% CI 0.17 to 0.19) for weekday-operated patients. These differences were independent of any differences in patient age, gender, American Society of Anaesthesiologists grade, surgeon seniority, surgical and anaesthetic practices, and thromboprophylaxis choice in weekend versus weekday-operated patients. CONCLUSION: The 30-day mortality rate after elective joint arthroplasty is low. Surgery performed at the weekend is associated with lower post-operative mortality versus operations performed on a weekday. Cite this article: Bone Joint J 2017;99-B:1618-28.

WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis.

OBJECTIVE: Increased Wisp1 expression was previously reported in experimental and human osteoarthritis (OA). Moreover, adenoviral overexpression of Wisp1 in naïve mouse knee joints resulted in early OA-like cartilage lesions. Here, we determined how the matricellular protein WISP1 is involved in the pathology that occurs in the complex osteoarthritic environment with aging and experimental OA in wild type (WT) and Wisp1-/- mice. METHODS: WT and Wisp1-/- mice were aged or experimental OA was induced with intraarticular collagenase injection, destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT). Joint pathology was assessed using histology and microCT. Protease expression was evaluated with qRT-PCR and activity was determined by immunohistochemical staining of the aggrecan neoepitope NITEGE. Protease expression in human end-stage OA synovial tissue was determined with qRT-PCR after stimulation with WISP1. RESULTS: With aging, spontaneous cartilage degeneration in Wisp1-/- was not decreased compared to their WT controls. However, we observed significantly decreased cartilage degeneration in Wisp1-/- mice after induction of three independent experimental OA models. While the degree of osteophyte formation was comparable between WT and Wisp1-/- mice, increased cortical thickness and reduced trabecular spacing was observed in Wisp1-/- mice. In addition, we observed decreased MMP3/9 and ADAMTS4/5 expression in Wisp1-/- mice, which was accompanied by decreased levels of NITEGE. In line with this, stimulation of human OA synovium with WISP1 increased the expression of various proteases. CONCLUSIONS: WISP1 plays an aggravating role in the development of post-traumatic experimental OA.

The role of complement inhibitors beyond controlling inflammation.

The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59. Complement activation is involved in both the development of and defence against cancer. COMP expression is pro-oncogenic, whereas CSMD1 and SUSD4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular COMP. CD59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic ß-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.

Synovial macrophages promote TGF-ß signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low-density lipoproteins.

OBJECTIVE: Low-density lipoproteins (LDL) in inflamed synovium is oxidized and taken-up by synoviocytes. In this study, we investigate whether direct injection of oxidized LDL (oxLDL) into a normal murine knee joint induces joint pathology and whether synovial macrophages are involved in that process. DESIGN: Synovium was obtained from end-stage osteoarthritis (OA) patients in order to analyze LDL-uptake. Murine knee joints were injected five consecutive days with oxLDL, LDL, or vehicle (phosphate buffered saline (PBS)). This procedure was repeated in mice depleted of synovial macrophages by intra-articular injection of clodronate liposomes 7 days prior to the consecutive injections. Joint pathology was investigated by immunohistochemistry, flow cytometry (FCM) and synovial RNA expression and protein production. RESULTS: Synovial tissue of OA patients showed extensive accumulation of apolipoprotein B. Multiple injections of oxLDL in murine knee joints significantly increased TGF-ß activity in synovial wash-outs, but did not induce catabolic or inflammatory processes. In contrast, repeated injections of oxLDL in macrophage-depleted knee joints led to increased synovial thickening in combination with significantly upregulated protein and RNA levels of CCL2 and CCL3. FCM-analyses revealed increased presence of monocytes and neutrophils in the synovium, which was confirmed by immunohistochemistry. Also protein levels of S100A8/A9 were significantly increased in synovial wash-outs of oxLDL-injected joints, as was expression of aggrecanase-induced neo-epitopes. Interestingly, no raise in TGF-ß concentrations was measured in macrophage-depleted joints. CONCLUSIONS: OxLDL can affect joint pathology, since synovial macrophages promote anabolic processes after oxLDL injections. In absence of synovial macrophages, however, oxLDL induces production of pro-inflammatory mediators and aggrecanase activity combined with increased influx of monocytes and neutrophils.