ResearchPad - osteoarthritis https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Canine hip dysplasia screening: Comparison of early evaluation to final grading in 231 dogs with Fédération Cynologique Internationale A and B]]> https://www.researchpad.co/article/elastic_article_15741 This study aimed to verify if a significant difference exists between parameters in the early evaluation of normal and near-normal hip joints, to evaluate the influence of age and breed on the parameters, and to clarify the usefulness of a total score for differentiating between Fédération Cynologique Internationale (FCI) grade A and B hips.MethodsA total of 231 dogs were classified according to whether they had FCI A or B hips at adulthood, with measurements obtained at 14–28 weeks of age. The total score was calculated by the summation of the following quantitative parameters: angle of subluxation (AS), angle of reduction (AR), laxity index (LI), and dorsal acetabular rim slope (DARS). Logistic regression analysis was performed to establish the probability of the study population to develop an FCI B hip based on the total score. This was repeated for the highest score in combination with the worst-rated hip and once more for breeds.ResultsNo correlation between age and the parameters was found in the cohort, or for FCI A and B. The values of all the parameters were significantly lower in the FCI A group than in the FCI B group (AR: 4.42° ± 6.0° vs 7.62° ± 7.2°; AS: 0.45° ± 1.9° vs 1.55° ± 3.8°; LI: 0.32 ± 0.1 vs 0.36 ± 0.1; DARS: 3.30° ± 1.8° vs 3.77° ± 1.9°; TS: 11.47 ± 8.3 vs 16.65 ± 10.9). Labrador Retrievers and Golden Retrievers showed significant differences between parameters for both FCI grades. The range, where FCI A and B hips can be predicted on the basis of the total score, was different when assessed for the entire cohort, Labrador Retrievers, and Golden Retrievers.Clinical significanceOur results show that even in normal and near-normal hips, the parameters significantly differed in the early evaluation. Moreover, cutoff values should be set for different breeds in the prediction of the FCI grade during early evaluation for a better breeding selection regarding canine hip dysplasia, one of the most common orthopedic diseases among large and giant breed dogs. ]]> <![CDATA[Reduction of osteoarthritis severity in the temporomandibular joint of rabbits treated with chondroitin sulfate and glucosamine]]> https://www.researchpad.co/article/N10336f10-2066-4958-9182-9e228dac929f

Osteoarthritis is a degenerative disease that causes substantial changes in joint tissues, such as cartilage degeneration and subchondral bone sclerosis. Chondroitin sulfate and glucosamine are commonly used products for the symptomatic treatment of osteoarthritis. The aim of the present study was to investigate the effects of these products when used as structure-modifying drugs on the progression of osteoarthritis in the rabbit temporomandibular joint. Thirty-six New Zealand rabbits were divided into 3 groups (n = 12/group): control (no disease); osteoarthritis (disease induction); and treatment (disease induction and administration of chondroitin sulfate and glucosamine). Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate. Animals were killed at 30 and 90 days after initiation of therapy. The treatment was effective in reducing disease severity, with late effects and changes in the concentration of glycosaminoglycans in the articular disc. The results indicate that chondroitin sulfate and glucosamine may have a structure-modifying effect on the tissues of rabbit temporomandibular joints altered by osteoarthritis.

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<![CDATA[Osteoarthritic Milieu Affects Adipose‐Derived Mesenchymal Stromal Cells]]> https://www.researchpad.co/article/Ndc5fe0ee-7ead-4afd-b603-8f3a1f34a315

ABSTRACT

The objective of this study was to define the effects of osteoarthritic (OA) milieu on good manufactured practice‐adipose‐derived mesenchymal stromal cells (GMP‐ASC) that are commonly utilized in cell therapies. Two different OA milieu: OA synovial fluid (SF) and OA‐conditioned medium (CM) from synoviocytes were used to treat GMP‐ASC both in normoxia or hypoxia. GMP‐ASC were tested for cell migration, proliferation, cytokine receptors expression (CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR5, IL6R), and cytokines (CXCL8/IL8, CXCL10/IP10, CXCL12/SDF‐1, CCL2/MCP1, CCL3/MIP1α, CCL4/MIP1β, CCL5/RANTES, IL6) release. Healthy SF was used as controls. We demonstrated that GMP‐ASC show an increase in proliferation, migration, and modulation of CXCR1, CXCR3, CCR1, and CCR5 receptors in hypoxic condition. Moreover, GMP‐ASC migration increased 15‐fold when treated either with OA‐SF or OA‐CM compared with healthy SF both in normoxia and hypoxia. GMP‐ASC treated in both OA milieu showed an increase in CXCR3, CCR3, and IL6R and a decrease in CCR1 and CCR2 receptors. In OA‐SF, we detected higher amount of CXCL10/IP10 than in OA‐CM, while CCL2/MCP1 and CCL4/MIP1β were higher in OA‐CM compared with OA‐SF. CXCL10/IP10 was the only chemokine of the OA milieu, which was down‐modulated after treatment with GMP‐ASC. In conclusion, we demonstrated specific effects of OA milieu on both GMP‐ASC proliferation, migration, and cytokine receptor expression that were strictly dependent on the inflammatory and hypoxic environment. The use of characterized OA milieu is crucial to define the therapeutic effect of GMP‐ASC and indicates that CXCL10/IP10–CXCR3 axis is partially involved in the GMP‐ASC effect on synovial macrophages. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 38:336‐347, 2020

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<![CDATA[pyKNEEr: An image analysis workflow for open and reproducible research on femoral knee cartilage]]> https://www.researchpad.co/article/N0686bd46-1746-4f66-8610-270f1b75b482

Transparent research in musculoskeletal imaging is fundamental to reliably investigate diseases such as knee osteoarthritis (OA), a chronic disease impairing femoral knee cartilage. To study cartilage degeneration, researchers have developed algorithms to segment femoral knee cartilage from magnetic resonance (MR) images and to measure cartilage morphology and relaxometry. The majority of these algorithms are not publicly available or require advanced programming skills to be compiled and run. However, to accelerate discoveries and findings, it is crucial to have open and reproducible workflows. We present pyKNEEr, a framework for open and reproducible research on femoral knee cartilage from MR images. pyKNEEr is written in python, uses Jupyter notebook as a user interface, and is available on GitHub with a GNU GPLv3 license. It is composed of three modules: 1) image preprocessing to standardize spatial and intensity characteristics; 2) femoral knee cartilage segmentation for intersubject, multimodal, and longitudinal acquisitions; and 3) analysis of cartilage morphology and relaxometry. Each module contains one or more Jupyter notebooks with narrative, code, visualizations, and dependencies to reproduce computational environments. pyKNEEr facilitates transparent image-based research of femoral knee cartilage because of its ease of installation and use, and its versatility for publication and sharing among researchers. Finally, due to its modular structure, pyKNEEr favors code extension and algorithm comparison. We tested our reproducible workflows with experiments that also constitute an example of transparent research with pyKNEEr, and we compared pyKNEEr performances to existing algorithms in literature review visualizations. We provide links to executed notebooks and executable environments for immediate reproducibility of our findings.

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<![CDATA[The gut microbiome-joint connection: implications in osteoarthritis]]> https://www.researchpad.co/article/N256dc247-6528-4e7a-b707-0d7658b0a0f1

Supplemental Digital Content is available in the text

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<![CDATA[Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis]]> https://www.researchpad.co/article/5c9bc279d5eed0c484ee3f5b

Objective

To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).

Methods

Patients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates.

Results

Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI –1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67).

Conclusion

Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo.

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<![CDATA[RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage]]> https://www.researchpad.co/article/5c82b297d5eed0c484e5a0f5

Objective

To uncover the microRNA (miRNA) interactome of the osteoarthritis (OA) pathophysiological process in the cartilage.

Methods

We performed RNA sequencing in 130 samples (n=35 and n=30 pairs for messenger RNA (mRNA) and miRNA, respectively) on macroscopically preserved and lesioned OA cartilage from the same patient and performed differential expression (DE) analysis of miRNA and mRNAs. To build an OA-specific miRNA interactome, a prioritisation scheme was applied based on inverse Pearson’s correlations and inverse DE of miRNAs and mRNAs. Subsequently, these were filtered by those present in predicted (TargetScan/microT-CDS) and/or experimentally validated (miRTarBase/TarBase) public databases. Pathway enrichment analysis was applied to elucidate OA-related pathways likely mediated by miRNA regulatory mechanisms.

Results

We found 142 miRNAs and 2387 mRNAs to be differentially expressed between lesioned and preserved OA articular cartilage. After applying prioritisation towards likely miRNA-mRNA targets, a regulatory network of 62 miRNAs targeting 238 mRNAs was created. Subsequent pathway enrichment analysis of these mRNAs (or genes) elucidated that genes within the ‘nervous system development’ are likely mediated by miRNA regulatory mechanisms (familywise error=8.4×10−5). Herein NTF3 encodes neurotrophin-3, which controls survival and differentiation of neurons and which is closely related to the nerve growth factor.

Conclusions

By an integrated approach of miRNA and mRNA sequencing data of OA cartilage, an OA miRNA interactome and related pathways were elucidated. Our functional data demonstrated interacting levels at which miRNA affects expression of genes in the cartilage and exemplified the complexity of functionally validating a network of genes that may be targeted by multiple miRNAs.

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<![CDATA[Systems biology reveals how altered TGFβ signalling with age reduces protection against pro-inflammatory stimuli]]> https://www.researchpad.co/article/5c536b3fd5eed0c484a4846b

Osteoarthritis (OA) is a degenerative condition caused by dysregulation of multiple molecular signalling pathways. Such dysregulation results in damage to cartilage, a smooth and protective tissue that enables low friction articulation of synovial joints. Matrix metalloproteinases (MMPs), especially MMP-13, are key enzymes in the cleavage of type II collagen which is a vital component for cartilage integrity. Transforming growth factor beta (TGFβ) can protect against pro-inflammatory cytokine-mediated MMP expression. With age there is a change in the ratio of two TGFβ type I receptors (Alk1/Alk5), a shift that results in TGFβ losing its protective role in cartilage homeostasis. Instead, TGFβ promotes cartilage degradation which correlates with the spontaneous development of OA in murine models. However, the mechanism by which TGFβ protects against pro-inflammatory responses and how this changes with age has not been extensively studied. As TGFβ signalling is complex, we used systems biology to combine experimental and computational outputs to examine how the system changes with age. Experiments showed that the repressive effect of TGFβ on chondrocytes treated with a pro-inflammatory stimulus required Alk5. Computational modelling revealed two independent mechanisms were needed to explain the crosstalk between TGFβ and pro-inflammatory signalling pathways. A novel meta-analysis of microarray data from OA patient tissue was used to create a Cytoscape network representative of human OA and revealed the importance of inflammation. Combining the modelled genes with the microarray network provided a global overview into the crosstalk between the different signalling pathways involved in OA development. Our results provide further insights into the mechanisms that cause TGFβ signalling to change from a protective to a detrimental pathway in cartilage with ageing. Moreover, such a systems biology approach may enable restoration of the protective role of TGFβ as a potential therapy to prevent age-related loss of cartilage and the development of OA.

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<![CDATA[Which osteoarthritic gait features recover following total knee replacement surgery?]]> https://www.researchpad.co/article/5c79afe0d5eed0c4841e38ee

Background

Gait analysis can be used to measure variations in joint function in patients with knee osteoarthritis (OA), and is useful when observing longitudinal biomechanical changes following Total Knee Replacement (TKR) surgery. The Cardiff Classifier is an objective classification tool applied previously to examine the extent of biomechanical recovery following TKR. In this study, it is further developed to reveal the salient features that contribute to recovery towards healthy function.

Methods

Gait analysis was performed on 30 patients before and after TKR surgery, and 30 healthy controls. Median TKR follow-up time was 13 months. The combined application of principal component analysis (PCA) and the Cardiff Classifier defined 18 biomechanical features that discriminated OA from healthy gait. Statistical analysis tested whether these features were affected by TKR surgery and, if so, whether they recovered to values found for the controls.

Results

The Cardiff Classifier successfully discriminated between OA and healthy gait in all 60 cases. Of the 18 discriminatory features, only six (33%) were significantly affected by surgery, including features in all three planes of the ground reaction force (p<0.001), ankle dorsiflexion moment (p<0.001), hip adduction moment (p = 0.003), and transverse hip angle (p = 0.007). All but two (89%) of these features remained significantly different to those of the control group after surgery.

Conclusions

This approach was able to discriminate gait biomechanics associated with knee OA. The ground reaction force provided the strongest discriminatory features. Despite increased gait velocity and improvements in self-reported pain and function, which would normally be clinical indicators of recovery, the majority of features were not affected by TKR surgery. This TKR cohort retained pre-operative gait patterns; reduced sagittal hip and knee moments, decreased knee flexion, increased hip flexion, and reduced hip adduction. The changes that were associated with surgery were predominantly found at the ankle and hip, rather than at the knee.

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<![CDATA[Validation of the Fitbit Charge 2 compared to the ActiGraph GT3X+ in older adults with knee osteoarthritis in free-living conditions]]> https://www.researchpad.co/article/5c5b52a5d5eed0c4842bcd46

Objective

To evaluate physical activity (PA) and sedentary time in subjects with knee osteoarthritis (OA) measured by the Fitbit Charge 2 (Fitbit) and a wrist-worn ActiGraph GT3X+ (AGW) compared to the hip-worn ActiGraph (AGH).

Design

We recruited a cohort of subjects with knee OA from rheumatology clinics. Subjects wore the AGH for four weeks, AGW for two weeks, and Fitbit for two weeks over a four-week study period. We collected accelerometer counts (ActiGraphs) and steps (ActiGraphs, Fitbit) and calculated time spent in sedentary, light, and moderate-to-vigorous activity. We used triaxial PA intensity count cut-points from the literature for ActiGraph and a stride length-based cadence algorithm to categorize Fitbit PA. We compared Fitbit wear times calculated from a step-based algorithm and a novel algorithm that incorporates steps and heart rate (HR).

Results

We enrolled 15 subjects (67% female, mean age 68 years). Relative to AGH, Fitbit, on average, overestimated steps by 39% and sedentary time by 37% and underestimated MVPA by 5 minutes. Relative to AGH, AGW overestimated steps 116%, underestimated sedentary time by 66%, and captured 281 additional MVPA minutes. The step-based wear time Fitbit algorithm captured 14% less wear time than the HR-based algorithm.

Conclusions

Fitbit overestimates steps and underestimates MVPA in knee OA subjects. Cut-offs validated for AGW should be developed to support the use of AGW for PA assessment. The HR-based Fitbit algorithm captured more wear time than the step-based algorithm. These data provide critical insight for researchers planning to use commercially-available accelerometers in pragmatic studies.

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<![CDATA[The prevalence of osteoarthritis: Higher risk after transfemoral amputation?—A database analysis with 1,569 amputees and matched controls]]> https://www.researchpad.co/article/5c50c47bd5eed0c4845e87f8

Background

Several studies have shown that patients with a unilateral amputation have an increased risk of developing osteoarthritis (OA) in the knee of their sound leg. OBJECTIVE: The first objective was to investigate whether amputees are more frequently affected by gon-, cox- or polyarthritis as well as back pain or spinal disorders. We hypothesized that mobile and active transfemoral amputees more often experience OA and spinal disorders than non-amputees. The second objective was to compare the mean age of the patients with OA.

Patients

Patients with a unilateral transfemoral amputation (n = 1,569) and five abled-body control groups (each n = 1,569) matched in terms of age and gender resulting in total of 9,414 participants.

Methods

Groups were analyzed regarding the prevalence of six selected diagnoses regarding musculoskeletal disorders.

Results

A significantly decreased prevalence of OA and specific disorders of the spine in transfemoral amputees compared to a control group was found. The amputees with OA are significantly younger than patients with OA in the control group.

Conclusion

The results from the presented study contradict previously published literature. Apparently circumstances of life play an important role, like physical work and strenuous activities which are likely to be underrepresented in the amputee group. The results of the study need to be used cautiously due to the major limitation of the study which is the lack of detail in individual patients caused by the methodology.

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<![CDATA[Exercise-induced hypoalgesia: A meta-analysis of exercise dosing for the treatment of chronic pain]]> https://www.researchpad.co/article/5c3fa5fbd5eed0c484caac27

Objective

Increasing evidence purports exercise as a first-line therapeutic for the treatment of nearly all forms of chronic pain. However, knowledge of efficacious dosing respective to treatment modality and pain condition is virtually absent in the literature. The purpose of this analysis was to calculate the extent to which exercise treatment shows dose-dependent effects similar to what is seen with pharmacological treatments.

Methods

A recently published comprehensive review of exercise and physical activity for chronic pain in adults was identified in May 2017. This report reviewed different physical activity and exercise interventions and their effectiveness in reducing pain severity and found overall modest effects of exercise in the treatment of pain. We analyzed this existing data set, focusing specifically on the dose of exercise intervention in these studies. We re-analyzed data from 75 studies looking at benefits of time of exercising per week, frequency of exercise per week, duration of intervention (in weeks), and estimated intensity of exercise.

Results

Analysis revealed a significant positive correlation with exercise duration and analgesic effect on neck pain. Multiple linear regression modeling of these data predicted that increasing the frequency of exercise sessions per week is most likely to have a positive effect on chronic pain patients.

Discussion

Modest effects were observed with one significant correlation between duration and pain effect for neck pain. Overall, these results provide insufficient evidence to conclude the presence of a strong dose effect of exercise in pain, but our modeling data provide tes predictions that can be used to design future studies to explicitly test the question of dose in specific patient populations.

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<![CDATA[Intraarticular Injection of a Cross-Linked Sodium Hyaluronate Combined with Triamcinolone Hexacetonide (Cingal) to Provide Symptomatic Relief of Osteoarthritis of the Knee: A Randomized, Double-Blind, Placebo-Controlled Multicenter Clinical Trial]]> https://www.researchpad.co/article/5c354a51d5eed0c484dbd37a

Objective:

To evaluate the efficacy and safety of an intraarticular injection of Cingal (Anika Therapeutics, Inc., Bedford, MA) compared with Monovisc (Anika Therapeutics, Inc., Bedford, MA) or saline for the treatment of knee osteoarthritis.

Design:

This multicenter, double-blind, saline-controlled clinical trial randomized subjects with knee osteoarthritis (Kellgren-Lawrence grades I-III) to a single injection of Cingal (4 mL, 88 mg hyaluronic acid [HA] plus 18 mg triamcinolone hexacetonide [TH]), Monovisc (4 mL, 88 mg HA), or saline (4 mL, 0.9%). The primary efficacy outcome was change in WOMAC (Western Ontario and McMaster Universities Arthritis Index) Pain Score through 12 weeks with Cingal versus saline. Secondary outcomes included Patient and Evaluator Global Assessments, OMERACT-OARSI Responder index, and WOMAC Total, Stiffness, and Physical Function scores through 26 weeks.

Results:

A total of 368 patients were treated (Cingal, n = 149; Monovisc, n = 150; saline, n = 69). Cingal improvement from baseline was significantly greater than saline through 12 weeks (P = 0.0099) and 26 weeks (P = 0.0072). WOMAC Pain was reduced by 70% at 12 weeks and by 72% at 26 weeks with Cingal. Significant improvements were found in most secondary endpoints for pain and function at most time points through 26 weeks. At 1 and 3 weeks, Cingal was significantly better than Monovisc for most endpoints; Cingal and Monovisc were similar from 6 weeks through 26 weeks. A low incidence of related adverse events was reported.

Conclusions:

Cingal provides immediate and long-term relief of osteoarthritis-related pain, stiffness, and function, significant through 26 weeks compared to saline. Cingal had similar immediate advantages compared with HA alone, while showing benefit comparable to HA at 6 weeks and beyond.

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<![CDATA[Quality indicators for ambulatory care for older adults with diabetes and comorbid conditions: A Delphi study]]> https://www.researchpad.co/article/5c1c0ae5d5eed0c484426dce

Background

An increasing number of people are living with multiple chronic conditions and it is unclear which quality indicators should be used to guide care for this population.

Objective

To critically appraise and select the most appropriate set of quality indicators for ambulatory care for older adults with five selected disease combinations.

Methods

A two-round web-based Delphi process was used to critically appraise and select quality of care indicators for older adults with diabetes and comorbidities. A fifteen-member Canadian expert panel with broad geographical and clinical representation participated in this study. The panel evaluated process indicators for meaningfulness, potential for improvements in clinical practice, and overall value of inclusion, while outcome indicators were evaluated for importance, modifiability and overall value of inclusion. A 70% agreement threshold was required for high consensus, and 60–69% for moderate consensus as measured on a 5-point Likert type scale.

Results

Twenty high-consensus and nineteen medium-consensus process and outcome indicators were selected for assessing care for older adults with selected disease combinations, including 1) concordant (conditions with a common management plan), 2) discordant (conditions with unrelated management plans), and 3) both types. Panelists reached rapid consensus on quality indicators for care for older adults with concordant comorbid conditions, but not for those with discordant conditions. All selected indicators assess clinical aspects of care. The feedback from the panelists emphasized the importance of developing indicators related to patient-centred aspects of care, including patient self-management, education, patient-physician relationships, and patient’s preferences.

Conclusions

The selected quality indicators are not intended to provide a comprehensive tool set for measuring quality of care for older adults with selected disease combinations. The recommended indicators address clinical aspects of care and can be used as a starting point for ambulatory care settings and development of additional quality indicators.

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<![CDATA[Deficiency of the pattern-recognition receptor CD14 protects against joint pathology and functional decline in a murine model of osteoarthritis]]> https://www.researchpad.co/article/5c0841d4d5eed0c484fcadbf

Objective

CD14 is a monocyte/macrophage pattern-recognition receptor that modulates innate inflammatory signaling. Soluble CD14 levels in knee OA synovial fluids are associated with symptoms and progression of disease. Here we investigate the role of this receptor in development of OA using a murine joint injury model of disease.

Methods

10-week-old Male C57BL/6 (WT) and CD14-deficient (CD14-/-) mice underwent destabilization of the medial meniscus (DMM) surgery to induce OA. Joint histopathology was used to examine cartilage damage, and microCT to evaluate subchondral bone (SCB) remodeling at 6 and 19 weeks after surgery. Synovial and fat pad expression of macrophage markers (F4/80, CD11c, CD68, iNOS, CCR7, CD163 and CD206) was assessed by flow cytometry and droplet digital (dd)PCR. Changes in locomotive activity indicative of joint pain were evaluated longitudinally up to 16 weeks by automated behavioral analysis.

Results

Early cartilage damage scores 6 weeks post-DMM were similar in both strains (Mean score ±SEM WT: 4.667±1.38, CD14-/-: 4.6±0.6), but at 19 weeks were less severe in CD14-/- (6.0±0.46) than in WT mice (13.44±2.5, p = 0.0002). CD14-/- mice were protected from both age-related and post-surgical changes in SCB mineral density and trabecular thickness. In addition, CD14-/- mice were protected from decreases in climbing activity (p = 0.015 vs. WT, 8 weeks) observed after DMM. Changes in synovial/fat pad expression of CCR7, a marker of M1 macrophages, were slightly reduced post-DMM in the absence of CD14, while expression of CD68 (pan-macrophage marker) and CD163 (M2 marker) were unchanged.

Conclusion

CD14 plays an important role in progression of structural and functional features of OA in the DMM model, and may provide a new target for therapeutic development.

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<![CDATA[Clinical magnetic resonance-enabled characterization of mono-iodoacetate-induced osteoarthritis in a large animal species]]> https://www.researchpad.co/article/5b6dda0d463d7e7491b405e7

Introduction

Osteoarthritis (OA) is the most common form of arthritis. Medical and surgical treatments have yet to substantially diminish the global health and economic burden of OA. Due to recent advances in clinical imaging, including magnetic resonance imaging (MRI), a correlation has been established between structural joint damage and OA-related pain and disability. Existing preclinical animal models of OA are useful tools but each suffers specific roadblocks when translating structural MRI data to humans. Intraarticular injection of mono-iodoacetate (MIA) is a reliable, well-studied method to induce OA in small animals but joint size discrepancy precludes the use of clinical grade MRI to study structural disease. The porcine knee is suited for clinical MRI and demonstrates homology with humans. We set out to establish the first large animal model of MIA-induced knee OA in swine characterized by structural MRI.

Materials and methods

Yucatan swine (n = 27) underwent ultrasound-guided injection of knees with 1.2, 4, 12, or 40 mg MIA. MRI was performed at several time points over 12 weeks (n = 54 knees) and images were assessed according to a modified clinical grading scheme. Knees were harvested and graded up to 35 weeks after injection.

Results

MIA-injected knees (n = 25) but not control knees (n = 29) developed gross degeneration. A total of n = 6,000 MRI measurements were recorded by two radiologists. MRI revealed progressive cartilage damage, bone marrow edema, erosions, and effusions in MIA-injected knees. Lesion severity and progression was influenced by time, dose, and inter-individual variability.

Conclusions

Intraarticular injection of MIA produced structural knee degradation that was reliably characterized using clinical MRI in swine. Destruction was progressive and, similar to human OA, lesion severity was heterogeneous between and within treatment groups.

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<![CDATA[3D printing and high tibial osteotomy]]> https://www.researchpad.co/article/5c042628d5eed0c48467dcd8

  • High tibial osteotomy (HTO) is a relatively conservative surgical option in the management of medial knee pain. Thus far, the outcomes have been variable, and apparently worse than the arthroplasty alternatives when judged using conventional metrics, owing in large part to uncertainty around the extent of the correction planned and achieved.

  • This review paper introduces the concept of detailed 3D planning of the procedure, and describes the 3D printing technology that enables the plan to be performed.

  • The different ways that the osteotomy can be undertaken, and the varying guide designs that enable accurate registration are discussed and described. The system accuracy is reported.

  • In keeping with other assistive technologies, 3D printing enables the surgeon to achieve a preoperative plan with a degree of accuracy that is not possible using conventional instruments. With the advent of low dose CT, it has been possible to confirm that the procedure has been undertaken accurately too.

  • HTO is the ‘ultimate’ personal intervention: the amount of correction needed for optimal offloading is not yet completely understood.

  • For the athletic person with early medial joint line overload who still runs and enjoys life, HTO using 3D printing is an attractive option. The clinical effectiveness remains unproven.

Cite this article: EFORT Open Rev 2018;3 DOI: 10.1302/2058-5241.3.170075.

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<![CDATA[Trochlear dysplasia: imaging and treatment options]]> https://www.researchpad.co/article/5c04262bd5eed0c48467dd11

  • Recurrent patellar dislocation is a disabling condition, which can lead to articular cartilage injuries, osteochondral fractures, recurrent instability, pain, decreased activity and patellofemoral osteoarthritis. Trochlear dysplasia represents an important component of patellar dislocation.

  • Imaging provides an objective basis for the morphological abnormalities and thus allows determination of the surgical strategy according to the concept of ‘à la carte’ surgery.

  • The main surgical techniques of trochleoplasty are the sulcus deepening trochleoplasty, the ‘Bereiter’ trochleoplasty and the recession trochleoplasty.

  • At mid-term, all techniques have shown a postoperative improvement in clinical scores, with a low rate of recurrence of dislocation and a possible return to sport. But these techniques do not halt the progression of patellofemoral arthritis.

Cite this article: EFORT Open Rev 2018;3 DOI: 10.1302/2058-5241.3.170058

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<![CDATA[Positive Selection on the Osteoarthritis-Risk and Decreased-Height Associated Variants at the GDF5 Gene in East Asians]]> https://www.researchpad.co/article/5989dad8ab0ee8fa60bb8d6e

GDF5 is a member of the bone morphogenetic protein (BMP) gene family, and plays an important role in the development of the skeletal system. Variants of the gene are associated with osteoarthritis and height in some human populations. Here, we resequenced the gene in individuals from four geographically separated human populations, and found that the evolution of the promoter region deviated from neutral expectations, with the sequence evolution driven by positive selection in the East Asian population, especially the haplotypes carrying the derived alleles of 5′ UTR SNPs rs143384 and rs143383. The derived alleles of rs143384 and rs143383, which are associated with a risk of osteoarthritis and decreased height, have high frequencies in non-Africans and show strong extended haplotype homozygosity and high population differentiation in East Asian. It is concluded that positive selection has driven the rapid evolution of the two osteoarthritis osteoarthritis-risk and decreased height associated variants of the human GDF5 gene, and supports the suggestion that the reduction in body size during the terminal Pleistocene and Holocene period might have been an adaptive process influenced by genetic factors.

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<![CDATA[Transforming growth factor β1 enhances heme oxygenase 1 expression in human synovial fibroblasts by inhibiting microRNA 519b synthesis]]> https://www.researchpad.co/article/5989db52ab0ee8fa60bdc906

Background

Osteoarthritis (OA) is manifested by synovial inflammation and cartilage destruction that is directly linked to synovitis, joint swelling and pain. In the light of the role of synovium in the pathogenesis and the symptoms of OA, synovium-targeted therapy is a promising strategy to mitigate the symptoms and progression of OA. Transforming growth factor beta 1 (TGF-β1), a secreted homodimeric protein, possesses unique and potent anti-inflammatory and immune-regulatory properties in many cell types. Heme oxygenase 1 (HO-1) is an inducible anti-inflammatory and stress responsive enzyme that has been proven to prevent injuries caused by many diseases. Despite the similar anti-inflammatory profile and their involvement in the pathogenesis of arthritic diseases, no studies have as yet explored the possibility of any association between the expression of TGF-β1 and HO-1.

Methodology/Principal findings

TGF-β1-induced HO-1 expression was examined by HO-1 promoter assay, qPCR, and Western blotting. The siRNAs and enzyme inhibitors were utilized to determine the intermediate involved in the signal transduction pathway. We showed that TGF-β1 stimulated the synthesis of HO-1 in a concentration- and time-dependent manner, which can be mitigated by blockade of the phospholipase (PLC)γ/protein kinase C alpha (PKC)α pathway. We also showed that the expression of miRNA-519b, which blocks HO-1 transcription, is inhibited by TGF-β1, and the suppression of miRNA 519b could be reversed via blockade of the PLCγ/PKCα pathway.

Conclusions/Significance

TGF-β1 stimulated the expression of HO-1 via activating the PLCγ/PKCα pathway and suppressing the downstream expression of miRNA-519b. These results may shed light on the pathogenesis and treatment of OA.

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