"You don't put it down to arthritis": A qualitative study of the first symptoms recalled by individuals with knee osteoarthritis.

Objective: As part of the first phase of the OARSI Early-stage Symptomatic Knee Osteoarthritis (EsSKOA) initiative, we explored the first symptoms and experiences recalled by individuals with knee osteoarthritis (OA). Design: This qualitative study, informed by qualitative description, was a secondary analysis of focus groups (n â€‹= â€‹17 groups) and one-on-one interviews (n â€‹= â€‹3) conducted in 91 individuals living with knee OA as part of an international study to better understand the OA pain experience. In each focus group or interview, participants were asked to describe their first symptoms of knee OA. We inductively coded these transcripts and conducted thematic analysis. Results: Mean age of participants was 70 years (range 47-92) and 68 â€‹% were female. We developed four overarching themes: Insidious and Episodic Onset, Diverse Early Symptoms, Must be Something Else, and Adjustments. Participants described the gradual and intermittent way in which symptoms of knee OA developed over many years; many could not identify a specific starting point. Participants described diverse initial knee symptoms, including activity-exacerbated joint pain, stiffness and crepitus. Most participants dismissed early symptoms or rationalized their presence, employing various strategies to enable continued participation in recreational and daily activities. Few sought medical attention until physical functioning was demonstrably impacted. Conclusions: The earliest symptoms of knee OA are frequently insidious in onset, episodic and present long before individuals present to health professionals. These results highlight challenges to identifying people with knee OA early and support the development of specific classification criteria for EsSKOA to capture individuals at an early stage.

Synovial tissue perivascular edema is associated with altered gait patterns in patients with knee osteoarthritis.

OBJECTIVE: To explore mechanisms of mechanoinflammation, we investigated the association between the presence of knee synovial perivascular edema and gait biomechanics that serve as surrogate measures of knee load in patients with knee osteoarthritis (OA). DESIGN: Patients with symptomatic, radiographic knee OA and neutral to varus alignment undergoing total knee arthroplasty or high tibial osteotomy participated in this cross-sectional analysis. All participants underwent 3D gait analysis prior to surgery. Synovial biopsies were obtained during surgery for histopathological assessment. The association between the presence of synovial perivascular edema (predictor) and the external knee moment (outcome) in each orthogonal plane was analyzed using multivariate linear regression and polynomial mixed effects regression models, while adjusting for age, sex, BMI, and gait speed. RESULTS: Ninety-two patients with complete gait and histopathological data were included. When fitted over 100% of stance, regression models indicated substantial differences between patients with and without synovial perivascular edema for knee moments in frontal, sagittal and transverse planes. The knee adduction moment was higher in patients with edema from 16 to 74% of stance, with the largest difference at 33% of stance (ß = 6.87 Nm [95%CI 3.02, 10.72]); whereas the knee flexion-extension moment differed from 15 to 92% of stance, with the largest difference in extension at 60% of stance (ß = -10.80 Nm [95%CI -16.20, -5.40]). CONCLUSIONS: In patients with knee OA, the presence of synovial perivascular edema identified by histopathology is associated with aberrant patterns of knee loading throughout stance, supporting the link between biomechanics and synovial inflammation.

Transient anabolic effects of synovium in early post-traumatic osteoarthritis: a novel ex vivo joint tissue co-culture system for investigating synovium-chondrocyte interactions.

OBJECTIVE: Osteoarthritis (OA) is a serious joint disease with no disease-modifying medical treatment. To develop treatments targeting synovium, we must improve our understanding of the effects of OA-related changes in synovial physiology on joint tissue outcomes. The aim of this study was to investigate the effects of synovial pathology due to post-traumatic OA (PTOA) on articular chondrocyte physiology. METHODS: We first developed and validated a novel joint tissue co-culture system to model the biological interactions between synovium and articular chondrocytes. Whole-joint synovial tissue from a surgical rat model of PTOA vs sham and surgical-naïve controls was placed into a co-culture system with adult primary articular chondrocytes (n = 4-5). The effects of PTOA synovium on chondrocyte anabolic, inflammatory, and catabolic gene expression and sulfated glycosaminoglycan (sGAG) secretion and aggrecan synthesis were tested, and results from early and later stages of PTOA development were compared. RESULTS: Synovial injury by arthrotomy (sham surgery) alone decreased primary chondrocyte expression of genes including Col2a1 (0.36 ± 0.15-fold) and Acan (0.41 ± 0.28-fold). Early PTOA synovium rescued the suppression of Acan, induced increased sGAG secretion (3.94 ± 0.44 µg/mL vs surgery-naïve 2.41 ± 0.55 and sham 2.92 ± 0.73 µg/mL controls), and upregulated Mmp3 (3.73 ± 2.62-fold) and Prg4 (4.93 ± 4.29-fold). These effects were lost with later stage PTOA synovium. CONCLUSIONS: Early PTOA synovium induces transient anabolic responses in articular chondrocytes rather than pro-inflammatory responses that would require inhibition. These results suggest that PTOA synovium plays at least a partially protective role and that loss of these protective effects may contribute to PTOA progression.

Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging-Induced Osteoarthritis in Mice.

OBJECTIVE: Osteoarthritis (OA) results in pathologic changes in the joint tissue. The mechanisms driving disease progression remain largely unclear, and thus disease-modifying treatments are lacking. Pannexin 3 (Panx3) was identified as a potential mediator of cartilage degeneration in OA, and our previous study in mice indicated that deletion of the Panx3 gene delayed surgically induced cartilage degeneration. This study was undertaken to examine the role of Panx3 in other OA subtypes, particularly primary OA during aging, in a mouse model of aging-induced OA. METHODS: Wild-type (WT) and Panx3-/- C57BL/6J (Black-6) mice, ages 18-24 months, were analyzed by micro-computed tomography to investigate bone mineral density and body composition. Joints were harvested from the mice, and histopathologic analysis of the joint tissue for OA development was conducted with a specific focus on changes in articular cartilage, subchondral bone, and synovial tissue. RESULTS: Global loss of Panx3 in aging mice was not associated with increased mortality or changes in body composition. Mice lacking Panx3 had shorter appendicular skeletons than WT mice, but overall the body compositions appeared quite similar. Panx3 deletion dramatically accelerated cartilage degeneration and subchondral bone thickening with aging in both 18-month-old and 24-month-old mice, while promoting synovitis in 18-month-old mice. CONCLUSION: These observations in a mouse model of OA suggest that Panx3 has a protective role against the development of primary aging-associated OA. It appears that Panx3 has opposing context-specific roles in joint health following traumatic injury versus that associated with aging. These data strongly suggest that there are differences in the molecular pathways driving different subtypes of OA, and therefore a detailed understanding of these pathways could directly improve strategies for OA diagnosis, therapy, and research.

Association between changes in knee load and effusion-synovitis: evidence of mechano-inflammation in knee osteoarthritis using high tibial osteotomy as a model.

OBJECTIVE: Although mechanically-induced inflammation is an appealing explanation linking different etiologic factors in osteoarthritis (OA), clinical research investigating changes in both biomechanics and joint inflammation is limited. The purpose of this study was to evaluate the association between change in surrogate measures of knee load and knee effusion-synovitis in patients with medial compartment knee OA undergoing high tibial osteotomy (HTO). METHODS: Thirty-six patients with medial compartment knee OA and varus alignment underwent 3D gait analysis and 3T magnetic resonance imaging (MRI) preoperatively and 1 year after medial opening wedge HTO. Primary outcome measures were the change in the external knee adduction moment impulse during walking and change in knee suprapatellar effusion-synovitis volume manually segmented on MRI by one blinded assessor. RESULTS: Mean (SD) knee adduction moment impulse [24.0 (6.5) Nm•s] and knee effusion-synovitis volume [8976.7 (8016.9) mm3] suggested substantial preoperative medial knee load and inflammation. 1-year postoperative changes in knee adduction moment impulse [-10.1 Nm•s (95%CI: -12.7, -7.4)], and knee effusion-synovitis volume [-1856 mm3 (95%CI: -3830, 117)] were positively correlated [r = 0.60 (95% CI 0.34, 0.78)]. Simple linear regression suggested a 448 mm3 (95%CI: 241, 656) reduction in knee effusion-synovitis volume per 1 Nm•s reduction in knee adduction moment impulse. Change in knee adduction moment impulse explained 36% (R2 = 0.36) of the variance of change in knee effusion-synovitis volume. CONCLUSIONS: Reduction in medial knee load is positively associated with reduction in knee inflammation after HTO, suggesting the phenomenon of mechano-inflammation in patients with knee OA.

Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis.

OBJECTIVE: MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective was to sequence the miRNome in plasma from 91 patients with early [Kellgren-Lawrence (KL) grade 0 or 1 (n = 41)] or late [KL grade 3 or 4 (n = 50)] symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state. DESIGN: MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550. Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs. RESULTS: From 215 differentially expressed microRNAs (FDR < 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms. CONCLUSION: Sequencing of well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA.

Reliability and concurrent validity of three-dimensional ultrasound for quantifying knee cartilage volume.

Objective: The goal of this study was to test the reliability and validity of a handheld mechanical three-dimensional (3D) ultrasound (US) device for quantifying femoral articular cartilage (FAC) against the current clinical standard of magnetic resonance imaging (MRI). Design: Bilateral knee images of 25 healthy volunteers were acquired with 3D US and 3.0 T MRI. The trochlear FAC was segmented by two raters who repeated segmentations on five cases during separate sessions. MRI and 3D US segmentations were registered using a semi-automated surface-based registration algorithm, and MRI segmentations were trimmed to match the FAC region from 3D US. Intra- (n = 5) and inter-rater (n = 25) reliabilities were assessed using intraclass correlation coefficients (ICCs) calculated from FAC volumes. Relationships between MRI and 3D US were assessed using Spearman correlation and linear regression (n = 25). Results: MRI intra-rater ICCs were 0.97 (0.79, 1.00) and 0.90 (0.25, 0.99) for each rater with an inter-rater ICC of 0.83 (0.48, 0.94). 3D US intra-rater ICCs were 1.00 (0.98, 1.00) and 0.98 (0.84, 1.00) for each rater with an inter-rater ICC of 0.96 (0.90, 0.98). Spearman correlation and linear regression revealed a strong correlation ρ = 0.884 (0.746, 0.949) and regression R2 = 0.848 (0.750, 0.950). Conclusion: These results suggest 3D US demonstrates excellent intra- and inter-rater reliabilities and strong concurrent validity with MRI when quantifying healthy trochlear FAC volume. 3D US may reduce imaging costs and greatly improve feasibility of quantifying knee cartilage volume during knee arthritis clinical trials and patient care.

Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: a narrative review.

OBJECTIVE: Population-based cohort studies suggest an association between osteoarthritis (OA) and cerebrovascular disease, yet the mechanisms underlying vascular comorbidities in OA remain unclear. The purpose of this narrative review is to discuss the literature examining inflammation in OA with a focus on physiological mechanisms, and whether overlapping mechanisms exist in cerebrovascular dysfunction. METHOD: A literature search was conducted in PubMed using combinations of search terms: osteoarthritis, cerebrovascular (disease/dysfunction/risk), cardiovascular (disease/dysfunction/risk), aging/ageing, inflammation, inflammatory mediators, cytokine, c-reactive protein, interleukin, advanced glycation end-products, metabolic syndrome, reactive oxidative species, cognitive impairment, (vascular-related) dementia, small cerebral vessel disease, endothelial function, blood-brain barrier, gender/sex, hypertension, peripheral vascular health, and physical activity. Reference lists of identified articles were also researched manually. RESULTS: Overlapping inflammatory factors that may contribute to onset and progression of both OA and cerebrovascular dysfunction are presented. We describe oxidative mechanisms involving pro-inflammatory cytokines and oxidative species, advanced glycation end-products, sex hormones, microvascular dysfunction and osteoprotegerin, and their specific roles in potentially contributing to OA and cerebrovascular dysfunction. CONCLUSION: Synthesis of the current literature suggests future investigations may benefit from directly testing cerebrovascular hemodynamics and cognitive function in individuals with or at risk of OA to elucidate common physiological mechanisms.

Osteoarthritis year in review 2017: biology.

This Year in Review was derived from a personal selection of articles investigating biological mechanisms of osteoarthritis (OA) and presented at the OARSI World Congress on April 30, 2017. Selected articles were published between the March, 2016 and April, 2017 OARSI meetings. PubMed/MEDLINE searches were performed using the terms "osteoarthritis", "cartilage", "subchondral bone", "synovium", "synovitis", and "ageing". Biomechanical, genetic, genomic, epigenomic, biomarker, clinical, imaging, and tissue engineering studies were excluded since they are covered by other articles in this series. Several new and emerging themes were identified. Incorporating new technologies such as designer genetic engineering, nanotechnology, and bio-selective nuclear medicine tracers into study designs helps to gain important insights into OA pathophysiology. Potentially critical differences exist between biological mechanisms of post-traumatic, age-associated, and metabolic phenotypes of OA. The concept of OA stages is highlighted, demonstrating how this may influence which biological mechanisms are at play and the need for strategic timing of treatment interventions. Not all inflammation is bad and fine-tuning a balance within inflammatory signaling mechanisms may be a path to regain joint homeostasis. Not only is the joint an organ system, sub-regions within each joint tissue, especially the joint lining, may play distinct roles in damage and repair. To accompany the review, the interaction among studies spanning multiple areas is summarized schematically.

Study of subchondral bone adaptations in a rodent surgical model of OA using in vivo micro-computed tomography.

OBJECTIVE: To non-invasively investigate the changes to epiphyseal bone occurring in a longitudinal pre-clinical model of osteoarthritis (OA) using in vivo micro-computed tomography (micro-CT). DESIGN: In vivo micro-CT images were acquired using a bench-top micro-CT scanner, which produces three-dimensional data with isotropic voxel spacing of 0.046 mm. Male rodents were scanned prior to surgical destabilization, consisting of anterior cruciate ligament transection and partial medial menisectomy (ACLX). Subsequent scans were performed every 4 weeks post-ACLX, for up to 5 months. Volumetric bone mineral density (vBMD) was measured in specific, anatomically segmented regions within each image. The ACLX rodent data were compared with the contralateral non-operated hind limb of the same animal, as well as a sham-operated group (SHAM) of animals, for each time point. End-point histology compared changes to cartilage and bone between the ACLX and control animals. RESULTS: The micro-CT protocol produced sufficient spatial resolution and signal-to-noise ratio (SNR=19) to quantify subchondral bone pathology, with an acceptable entrance exposure to radiation (0.36 Gy). Significantly lower vBMD was measured in the ACLX group, vs SHAM rodents, at 1, 4, and 5 months post-surgery (P<0.05). Qualitative observations of ACLX joints revealed significant loss of cartilage, subchondral bone cysts, and calcification of tendon similar to changes found in humans. CONCLUSIONS: This study demonstrates in vivo micro-CT as an effective method for investigating the development of rodent knee OA longitudinally. This method can be applied, in future pre-clinical trials, to non-destructively monitor the efficacy of pharmacological interventions.

Global analyses of gene expression in early experimental osteoarthritis.

OBJECTIVE: To analyze genome-wide changes in chondrocyte gene expression in a surgically induced model of early osteoarthritis (OA) in rats, to assess the similarity of this model to human OA, and to identify genes and mechanisms leading to OA pathogenesis. METHODS: OA was surgically induced in 5 rats by anterior cruciate ligament transection and partial medial meniscectomy. Sham surgery was performed in 5 additional animals, which were used as controls. Both groups underwent 4 weeks of forced mobilization, 3 times per week. RNA was extracted directly from articular chondrocytes in the OA (operated), contralateral, and sham-operated knees. Affymetrix GeneChip expression arrays were used to assess genome-wide changes in gene expression. Expression patterns of selected dysregulated genes, including Col2a1, Mmp13, Adamts5, Ctsc, Ptges, and Cxcr4, were validated by real-time polymerase chain reaction, immunofluorescence, or immunohistochemistry 2, 4, and 8 weeks after surgery. RESULTS: After normalization, comparison of OA and sham-operated samples showed 1,619 differentially expressed probe sets with changes in their levels of expression > or = 1.5-fold, 722 with changes > or = 2-fold, 135 with changes > or = 4-fold, and 20 with changes of 8-fold. Dysregulated genes known to be involved in human OA included Mmp13, Adamts5, and Ptgs2, among others. Several dysregulated genes (e.g., Reln, Phex, and Ltbp2) had been identified in our earlier microarray study of hypertrophic chondrocyte differentiation. Other genes involved in cytokine and chemokine signaling, including Cxcr4 and Ccl2, were identified. Changes in gene expression were also observed in the contralateral knee, validating the sham operation as the appropriate control. CONCLUSION: Our results demonstrate that the animal model mimics gene expression changes seen in human OA, supporting the relevance of newly identified genes and pathways to early human OA. We propose new avenues for OA pathogenesis research and potential targets for novel OA treatments, including cathepsins and cytokine, chemokine, and growth factor signaling pathways, in addition to factors controlling the progression of chondrocyte differentiation.