Early-stage Knee Osteoarthritis Research Articles

Lower extremity proprioceptive sensation in patients with early stage knee osteoarthritis: A comparative study

BackgroundKnee OA causes pain and proprioceptive impairment. The body acts as a closed kinetic chain, and deformation on the knee cannot only affect the knee joint but also can affect the other joints. ObjectiveTo assess the proprioception of lower extremity in early stage knee osteoarthritis compared with without knee osteoarthritis individuals. MethodsThe study sample consisted of 26 adults with early stage knee osteoarthritis and 26 subjects without knee osteoarthritis individuals. Western Ontario and McMaster Universities Osteoarthritis Index was used for clinical disease severity. Visual Analogue Scale was used for pain severity. Proprioception (position and motion sense) was measured by isokinetic dynamometer. ResultsWestern Ontario and McMaster Universities Osteoarthritis Index total score was 10.9 ± 5. Visual Analogue Scale scores during activity were found to be significantly higher than the scores at rest and night for both sides. Hip flexion and internal rotation joint position sense were significantly different between two groups (all p's < 0.05). Hip abduction, knee flexion, ankle and subtalar position sense, as well as hip and knee motion sense were similar between groups (all p's > 0.05). Ankle dorsiflexion and eversion motion sense were significantly different between two groups (all p's < 0.05). ConclusionsThis study demonstrated that the hip flexion and internal rotation position sense and ankle/subtalar joints motion sense may be affected on early stage of knee osteoarthritis. Investigation of the mechanism of proprioception for joints and also focusing on the longitudinal relationship between proprioception, knee OA disease and symptoms is recommended for future studies.

Effect of physical therapy on early knee osteoarthritis with medial meniscal posterior tear assessed by MRI T2 mapping and 3D-to-2D registration technique: A prospective intervention study

Objectives: The purpose of this study was to verify that exercise aimed at improving knee kinematics in early-stage knee osteoarthritis (OA) patients with medial meniscus posterior root tears (MMPRTs) reduces knee adduction angle during gait and prevents rapid cartilage degeneration in the medial compartment of the knee.Methods: Subjects were randomly assigned to an adapting alignment exercise (AAE) group, with the goal of improving knee kinematics, and a muscle training and exercise (MTE) group. Before the start of the six-month intervention and following its completion, we performed an analysis of knee kinematics during gait using a 3D-to-2D registration technique and identified the area of cartilage degeneration using MRI T2 mapping.Results: The amount of change between pre- and post-intervention measurements of the maximum angle of adduction was 0.48° (95% CI: −0.14, 1.09) in the MTE group and −0.40° (−0.84, 0.04) in the AAE group (p = .039). The amount of change in the area of cartilage degeneration according to MRI T2 mapping expressed as MTE/AAE group was 7.7 mm2 (−0.4, 15.8)/−2.7 mm2 (−10.8, 5.3) at the posterior knee (p = .043).Conclusion: AAE could be a potential treatment method that improves the natural course of knee OA with MMRPTs.

Increase in medial meniscal extrusion in the weight-bearing position observed on ultrasonography correlates with lateral thrust in early-stage knee osteoarthritis

BackgroundLateral thrust is known to be risk factors for knee osteoarthritis progression. Medial meniscus extrusion is also known to be risk factors for knee osteoarthritis progression; moreover, the amount of change in medial meniscus extrusion from non-weight bearing to weight bearing is an important factor for the progression of knee osteoarthritis. This study aimed to investigate the correlation between lateral thrust and the change in medial meniscus extrusion. MethodsIn total, 44 knees from 44 patients (mean age, 68.9 years) with knee osteoarthritis were divided into two groups according to the Kellgren–Lawrence grade: early-stage osteoarthritis (Kellgren–Lawrence = 2) and severe osteoarthritis (Kellgren–Lawrence = 3 or 4). The lateral thrust during gait, represented as the lateral acceleration peak immediately after heel strike, was recorded by an inertial sensor. The amount of change in medial meniscus extrusion, which was the difference between weight-bearing (unipedal standing) and non-weight-bearing (supine) conditions, was evaluated using ultrasonography. ResultsThe mean value of the lateral acceleration peak in the severe osteoarthritis group was higher than that of the early-stage osteoarthritis group (p < 0.05). The non-weight-bearing and weight-bearing medial meniscus extrusion in the severe OA group were significantly higher than those of the early-stage osteoarthritis group (p < 0.001). However, the amount of change in medial meniscus extrusion in severe osteoarthritis group was significantly lower than in the early-stage osteoarthritis group (p < 0.05). The amount of change in medial meniscus extrusion showed a significant correlation with the lateral acceleration peak in the early-stage osteoarthritis group (r = 0.56, p < 0.001). On the other hand, there was no significant correlation in the severe osteoarthritis group. ConclusionThe lateral thrust shows a positive correlation with the amount of change in medial meniscus extrusion by weight bearing in patients with early-stage knee osteoarthritis.

Research progress on subchondral bone lesions in degenerative knee osteoarthritis

The role of the subchondral bone in the pathophysiological processes of knee osteoarthritis(KOA)is receiving increasing attention.During the early stages of KOA, micro-fractures due to stress occurr with increased subchondral bone remodeling and decreased subchondral bone structural parameters, promoting the development of local microcirculatory disorders and atypical bone marrow lesions(BMLs). The micro-pores in cartilage provide pathways for blood vessel invasion into the deep layers of articular cartilage and subsequently bring in cartilage-degrading enzymes.With the pathogenesis of KOA, the loss of proteoglycans, which resist pressure to maintain the integrity of articular cartilage, results in stress overloading and then metabolic imbalances, leading to decreased bone resorption and increased bone formation.In the late stages of KOA, significant subchondral bone sclerosis further obstructs local blood microcirculation, which manifests as extended BMLs or increased signal intensity and even subchondral bone cysts.The acidic local environment impairs osteoblast function and erodes bone strength, contributing to subchondral bone collapse.Consequently, there is continued loss of the attached articular cartilage because of the positive feedback.Drug or surgical treatment aimed at cartilage protection should focus on functional modulation of osteoblasts and/or osteoclasts in the subchondral bone and the internal environment at different stages, instead of merely on the protection of articular cartilage. Key words: Cartilage; Osteoarthritis; Knee

Correlation network analysis shows divergent effects of a long-term, high-fat diet and exercise on early stage osteoarthritis phenotypes in mice

BackgroundObesity increases knee osteoarthritis (OA) risk through metabolic, inflammatory, and biomechanical factors, but how these systemic and local mediators interact to drive OA pathology is not well understood. We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice. We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups. MethodsMale C57BL/6J mice were fed a defined control (10% kcal fat) or high fat (HF) (60% kcal fat) diet from 6 to 37 weeks of age. At 25 weeks, one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study. Histology, micro computed tomography, and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology. These local variables were then compared to systemic metabolic (body mass, body fat, and glucose tolerance), inflammatory (serum adipokines and inflammatory mediators), and functional (mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis. Diet and exercise effects were evaluated by two-way analysis of variance. ResultsAn HF diet increased the infrapatellar fat pad size and posterior joint osteophytes, and wheel running primarily altered the subchondral cortical and trabecular bone. Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups. However, the coefficient of variation was ≥25% for many outcomes, and some mice in both diet groups developed moderate OA (≥33% maximum score). This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes. In wheel-running cohorts, an HF diet reduced the network size compared to the control diet group despite similar running distances, suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors. Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA. ConclusionDespite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations, diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA. These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease.

Gait kinematics for patients with early stage knee osteoarthritis in the approach project

Gait kinematics for patients with early stage knee osteoarthritis in the approach project

Osteophytes formation processes in early stage knee osteoarthritis in human

Purpose: Reduction of ADL by osteoarthritis of the knee (knee OA) is a major factor threatening healthy life expectancy. Thus, clarification of the pathology of knee OA is desired. We reported that cartilage part of osteophyte could be detected using T2 mapping MRI and medial meniscal extrusion (MME) was associated with medial tibial osteophyte evaluated by T2 mapping MRI in early-stage knee OA (Arthritis Res Ther, 19:201, 2017). However, there is no report showing cartilage part of osteophytes in early stage knee OA in human, histologically. The aim of this study was to investigate the morphological feature of osteophytes in human knee OA using cadavers. Methods: All cadavers were from persons who had donated their bodies for medical education and research to our university. Prior to donation, written consent was obtained from the individuals and families. The protocol for the present research project was approved by the Ethics Committee of our university. Fourteen left legs were collected from embalmed Japanese cadavers (3 males, 11 females; average age, 83.3±8.2 years of age), which were dissected by medical students in the gross anatomy course at Juntendo University School of Medicine. Knee joint was dissected out proximal and distal 10cm from the knee articular surface after skin removal. Anteroposterior view radiographs were taken and then evaluated according to the Kellgren-Lawrence (K/L) classification. Then, the patella and muscle were removed and the 2 cm width of medial parts of the knee joint remaining the medial collateral ligament were collected. They were fixed in 10% neutral buffered formalin, decalcified, and embedded in paraffin. The samples were cut into sections and stained with safranin-O and fast green. The histological features of medial tibial plateau (MTP) was quantified by histological grading scores. The cartilage degradation score used in the present study was the modified Mankin score (0-18) (Mankin, JBJS, 1971). The osteophyte formation score used in the present study was a score for its maturity with 5 degrees (0-4; grade 0: no osteophyte like lesion, grade 1: pre-cartilagious lesion, grade 2: predominantly cartilaginous, grade 3: mixed cartilage and bone, grade 4: predominantly bone), which was modified by the score for the evaluation of osteophyte in mouse model, as previously reported (Kamekura et al., Osteoarthritis Cartilage, 2005). Results: The severities of radiographic knee OA of the subjects in the present study were 7 (50.0%) for K/L grade 1, 5 (37.7%) for K/L grade 2, 2 (14.3%) for K/L grade 4, respectively. The cartilage degradation scores of the subjects were 4.1 [standard deviation (SD): 1.5] for K/L grade 1, 5.2 (1.3) for K/L grade 2, 15.0 (3.0) for K/L grade 4, respectively. Osteophytes were observed in all the samples of the subjects, regardless of the radiographic severity of knee OA. The osteophyte scores of the subjects were 7 (50.0%) for grade 1, 3 (21.4%) for grade 2, 2 (14.3%) for grade 3, and 2 (14.3%) for grade 4, respectively (Fig. 1). The histological sections with grade 4 of osteophytes were consisted of proliferative, pre-hypertrophic, hypertrophic, and ossification zones, while those with grade 1 were consisted of reduplication of synovial tissues. Conclusions: The histological examinations showed that osteophytes were existed in all the samples of the subjects, which showed the radiographic knee OA changes not only with K/L grade 2 to 4 but also with K/L grade 1. The developmental processes of the osteophyte in knee OA in human were similar to those observed in the growth plate in the murine model, which is the process similar to the endochondral ossification.

Role of synovial perlecan in osteophyte formation in early stage knee osteoarthritis

Role of synovial perlecan in osteophyte formation in early stage knee osteoarthritis

MicroRNA 27B-3P: role in extracellular matrix regulation in osteoarthritis synovial fibroblasts

Purpose: Synovial fibrosis is a key pathological event that contributes towards joint destruction, pain and stiffness associated with osteoarthritis (OA). Fibrosis is associated with the accumulation of excessive amount of extra-cellular matrix (ECM) resulting in tissue damage. Currently, endogenous mechanisms that play a key role in the initiation and progression of synovial fibrosis during OA are not well understood. We have previously shown that the expression of a small non-coding RNA called microRNA27b-3p (miR-27b-3p) is elevated in the synovial fluid of late-stage (Kellgren-Lawrence, KL score 3 & 4) compared to early-stage (KL score 1 & 2) radiographic knee OA patients. Furthermore, we also observed that miR-27b-3p is abundantly expressed in OA synovium (Y-H. Li, G. Tavallaee, et al. 2016). Since the role of miR-27b-3p in synovial pathology associated with OA has never been studied; we investigated if miR-27b-3p plays any role in ECM regulation in the OA synovium. Methods: Synovial tissues were obtained from OA patients undergoing total knee replacement with informed written consent. Primary OA synovial fibroblasts (major cell types present in the synovium) were isolated, cultured and transfected with miR-27b-3p mimic/inhibitor and subjected to qPCR arrays specific for ECM markers. Results obtained from arrays were further validated using quantitative-PCR analysis. For in vivo studies, mice were also subjected to DMM model of OA to determine the expression of miR-27b-3p during the time course of OA development in knee joint using in situ hybridization (ISH). Results: ECM-specific qPCR-arrays followed by validation of responsive genes by quantitative-PCR analysis revealed that miR-27b-3p mimic treatment resulted in a significant upregulation of key ECM genes including pro-collagen type-I (COL1A1), A disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS-8), Thrombospondin 1 (THBS1), fibronectin1 (FN1), Collagen 5 A 1 (COL5A1) and Collagen 14 A 1 (COL14A1) in OA Synovial fibroblasts. Furthermore, miR-27b-3p mimic resulted in a marked increase in type-I collagen protein expression; this effect was inhibited by miR-27b-3p inhibitor. Overall, these results suggest that miR-27b-3p may play a key role in the regulation of key ECM components in OA synovial fibroblasts. Next, we employed “Watson Discovery tool” to identify direct targets of miR-27b-3p to further elucidate its signalling pathway. This tool identified a panel of 11 genes including peroxisome proliferator-activated receptor gamma (PPARγ) as direct targets for miR-27b-3p. Indeed, we confirmed that miR-27b-3p mimic treatment results in a marked suppression of PPARγ expression, while inhibition of miR-27b-3p upregulates PPARγ, suggesting that miR-27b-3p may impart its ECM regulatory effect through modulation of PPARγ. Furthermore, ISH of DMM-induced OA mice knee joints further show that miR-27b-3p expression is prominent in the synovial lining and fibrocartilage compared to sham control mice in vivo. Conclusions: Our results thus far suggest that, in OA synovial fibroblasts, miR-27b-3p is involved in the regulation of key ECM components. Our data also suggest that miR-27b-3p may signal via negative regulation of PPARγ. Our ongoing studies are confirming if miR-27b-3p signalling via PPARγ controls ECM regulation in OA synovial fibroblasts. Our in vivo studies show that miR-27b-3p expression is elevated in the synovium during OA. To comprehensively investigate the endogenous role of miR-27b-3p in synovial pathology, we have intra-articularly injected mouse knee joints with the in-vivo grade mimic of miR-27b-3p to determine any changes in the synovium upon miR-27b-3p treatment in vivo.

Interleukin-17 is a potential contributor to the inflammatory environment in the OA joint

Purpose: Osteoarthritis (OA) has been historically viewed as a degenerative disease caused by ‘wear and tear’, with the loss of articular cartilage as the most important clinical feature. Modern imaging techniques have shown us over the last decade that OA is a multifactorial disorder that affects multiple tissues in the joint, including the subchondral bone and synovium. Synovitis is now increasingly recognised to be involved in OA pathogenesis, with in vitro studies showing production and release of pro-inflammatory cytokines (such as interleukin (IL)-6, IL-8, and IL-17, infiltration of mononuclear cells, and increased angiogenesis. This study aimed to establish whether the pro-inflammatory cytokine IL-17 contributes to the inflammatory environment within the OA joint. We hypothesized that IL-17 can contribute to inflammatory cell recruitment to the OA synovium and that IL-17 responsive stromal cell populations within the OA joint can further drive inflammation. Methods: Formalin-fixed paraffin-embedded synovial tissue from injured and early-stage knee OA patients was stained for IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC) as well as for the macrophage markers CD68 and CD206. Freshly isolated synovium from end-stage knee OA patients was digested for FACS analysis using a macrophage panel. Stromal cells from synovium (synovial fibroblasts) and cartilage (chondrocytes) from end-stage knee OA patients were cultured to passage 3 and assessed for IL-17R mRNA expression by RT-qPCR. In addition, these stromal cells were treated for 24h with 10 ng/ml rh IL-17 and RNA was harvested for RNA-Seq analysis. Results: We detected IL17RA and IL17RC mRNA in cultured chondrocytes and synovial fibroblasts from end-stage OA patients and showed that IL-17 receptors IL-17RA and IL-17RC are expressed in synovial tissue sections derived from injured and early-stage OA patients. While protein expression of IL-17RA was significantly higher in patients with a high synovitis score compared to a low synovitis score (p=0.012), IL-17RC did not show this difference (p=0.98). IL-17RA staining showed a trend toward correlation with CD68 (p=0.07) and correlated significantly with CD206 staining (p=0.004). IL-17RC did not correlated with CD206 (p=0.88), but showed a trend towards significance with CD206 (p=0.53). FACS data confirmed the presence of CD206+ macrophages in end-stage OA synovium. In cultured synovial fibroblasts and chondrocytes from end-stage OA patients, IL-17 treatment significantly upregulated the mRNA expression of several granulocyte-attracting and -regulating factors such as CCL2, CXCL3, CXCL6, and CXCL8. Conclusions: This study shows that IL-17 may contribute to the inflammatory environment in the joint by acting on synovial fibroblasts and chondrocytes to driving mononuclear cell influx. As IL-17 responsive cells are correlated with macrophage populations, IL-17 may be able to further drive inflammation by acting on these inflammatory cells as well as on synovial fibroblasts and chondrocytes.

Inflammation and Hypervascularization in a Large Animal Model of Knee Osteoarthritis: Imaging with Pathohistologic Correlation

PurposeTo evaluate if synovial inflammation and hypervascularization are present in a dog model of knee osteoarthritis and can be detected on conventional magnetic resonance imaging (MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), contrast-enhanced magnetic resonance imaging (CE-MRI), and quantitative digital subtraction angiography (Q-DSA) imaging. Materials and MethodsSix dogs underwent MRI and angiography of both knees before and 12 weeks after right knee anterior cruciate ligament injury. Synovial vascularity was evaluated on CE-MRI, DCE-MRI, and Q-DSA by 2 independent observers. Synovial inflammation and vascularity were histologically scored independently. Cartilage lesions and osteophytes were analyzed macroscopically, and cartilage volumetry was analyzed by MRI. Vascularity and osteoarthritis markers on imaging were compared before and after osteoarthritis generation, and between the osteoarthritis model and the control knee, using linear mixed models accounting for within-dog correlation. ResultsIn all knees, baseline imaging showed no abnormalities. Control knees did not develop significant osteoarthritis changes, synovial inflammation, or hypervascularization. In osteoarthritis knees, mean synovial enhancement score on CE-MR imaging increased by 13.1 ± 0.59 (P < .0001); mean synovial inflammation variable increased from 47.33 ± 18.61 to 407.97 ± 18.61 on DCE-MR imaging (P < .0001); and area under the curve on Q-DSA increased by 1058.58 ± 199.08 (P = .0043). Synovial inflammation, hypervascularization, and osteophyte formations were present in all osteoarthritis knees. Histology scores showed strong correlation with CE-MR imaging findings (Spearman correlation coefficient [SCC] = 0.742; P = .0002) and Q-DSA findings (SCC = 0.763; P < .0001) and weak correlation with DCE-MR imaging (SCC = -0.345; P = .329). Moderate correlation was found between CE-MR imaging and DSA findings (SCC = 0.536; P = .0004). ConclusionsIn this early-stage knee osteoarthritis dog model, synovial inflammation and hypervascularization were found on imaging and confirmed by histology.

Patients with early-stage knee osteoarthritis and knee pain have decreased hip abductor muscle strength while descending stairs.

This study aimed to investigate the association between hip abductor muscle strength and knee pain in patients with early-stage knee osteoarthritis (OA) while ascending and descending stairs. This cross-sectional study included individuals with early-stage knee OA (Kellgren/Lawrence grades 1 or 2). Knee pain while ascending and descending stairs was evaluated using a knee OA-related health domain measure (Japanese Knee Osteoarthritis Measure). Knee extension and hip abductor muscle strength were also evaluated. The association between hip abductor muscle strength and knee pain while ascending and descending stairs was evaluated using multiple regression analysis. A total of 157 participants were included in the final analysis. After the adjustment for age, sex, and knee extension strength, those with knee pain while descending stairs showed significantly decreased hip abductor muscle strength (β, - 0.09; 95% confidence interval [CI], - 0.19 to - 0.003). In contrast, after the adjustment for age, sex, and knee extension muscle strength, those with knee pain while ascending stairs did not have significantly decreased hip abductor muscle strength (β, - 0.06; 95% CI, - 0.15 to 0.02). Patients with early-stage knee OA and knee pain while descending stairs had significantly reduced hip abductor muscle strength.

The short-term effect of PRP on chronic pain in knee osteoarthritis.

The administration of platelet-rich plasma (PRP), which increases the release of growth factors targeting cartilage regeneration, is used in an effort to relieve pain in knee osteoarthritis (OA). This study measured the short-term efficacy of PRP on chronic pain in patients with OA of the knee. Patients with chronic knee pain and grade 2-4 knee OA based on the Kellgren-Lawrence (K-L) classification were enrolled in the study. A total of 60 knee joints of 42 patients who completed 3 doses of intraarticular PRP injections administered at intervals of 3 weeks were analyzed. The patients' pain was evaluated using a resting and activity visual analog scale (VAS) on day 0, and at week 3, 6, and 12. Of the 42 patients, 37 were female. The mean age and body mass index was 60.52+-10.41 years and 28.5+-9.71 kg/m2. A total of 18 patients had bilateral knee involvement, and 39 of the 60 knee joints were classified as K-L grade 3-4 OA. A significant improvement was observed in the mean resting and activity VAS scores at day 0 and week 12 (p<0.05). In K-L grade 2 patients, the day 0 and week 3 resting and activity VAS scores were significantly better than the grade 3-4 scores (p<0.05). It was observed that PRP injections provided a meaningful improvement in chronic knee pain in patients with knee OA throughout a 12-week period. The pain reduction response to PRP was better in patients with early-stage knee OA.

The Impact of Excluding Patients with End-Stage Knee Disease in Intra-Articular Hyaluronic Acid Trials: A Systematic Review and Meta-Analysis.

IntroductionThe Kellgren–Lawrence (K–L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease.MethodsWe conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K–L grade criteria. The primary outcome was mean change in pain from baseline at 4–13 weeks and 22–27 weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE).ResultsTwenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4–13 weeks [SMD = − 0.30, 95% CI − 0.44 to − 0.15, p < 0.0001] and within 22–27 weeks [SMD = − 0.27, 95% CI − 0.39 to − 0.16, p < 0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR = 1.76, 95% CI 1.16–2.67, p = 0.008].ConclusionIA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6 months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort.FundingFerring Pharmaceuticals.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0847-1) contains supplementary material, which is available to authorized users.

Knee osteoarthritis at the early stage: The four-week effect of lateral wedge insole on pain and risk of falls.

Background: Knee osteoarthritis (KOA) is associated with a decrease in function, increase in pain and risk of falls. Lateral wedge insole (LWI) is commonly prescribed in KOA to improve pain and function. Our study aimed to 1) evaluate the clinical symptoms and risk of falls in early KOA and compare with controls; 2) evaluate the immediate and four-week effect of LWI. Methods: A sample of 20 Persian dwelling individuals with early KOA and 19 matched controls were recruited. Pain with Visual Analogue Scale (VAS), Quality of life (QOL) with the knee injury and osteoarthritis outcome score, risk of falls with the Timed Up and Go (TUG) and static One-leg Balance (OLB) tests were assessed. The four-week effect of 5º LWI was considered for individuals with KOA. Independent t-test was done to report the between-group differences, and paired t-test was used to report the four-week effect of LWI. Results: At baseline, statistically significant higher scores for pain, lower scores for QOL, and higher risk of falls were observed in KOA compared to controls (p< 0.001). A significant statistical decrease was observed in pain, and risk of falls, and an increase in QOL in KOA after four-week effect of LWI compared to baseline (p< 0.001). Conclusion: People with early KOA showed higher pain and lower level of QOL that were associated with higher risk of falls. LWI may have the potential to improve clinical symptoms and reduce the risk of falls at the early stage of KOA.

Diagnostic performance of knee physical exam and participant-reported symptoms for MRI-detected effusion-synovitis among participants with early or late stage knee osteoarthritis: data from the Osteoarthritis Initiative

Evaluate the diagnostic performance of knee physical exam findings and participant-reported symptoms for MRI-detected effusion-synovitis (ES) among knees with early and late-stage osteoarthritis (OA). The Osteoarthritis Initiative (OAI) is a longitudinal study of participants with or at risk for knee OA. Two samples with MRI readings were available: 344 knees with early OA (312 participants) and 216 with late-stage OA (186 participants). Trained examiners performed bulge sign (BS) and patellar tap (PT) exams, and participants reported on knee swelling and pain with leg straightening. Effusion-synovitis on 3T non-contrast MRI was scored using the MRI Osteoarthritis Knee Score (MOAKS). Diagnostic performance of physical exam findings and symptoms was estimated with bootstrapped confidence intervals. For the early OA sample, the highest sensitivity for medium/large effusion-synovitis was achieved with a positive finding for any of the physical exam maneuvers and/or participant-reported symptoms (81.0 [95% CI: 70.0, 91.3]). Both knee symptoms in combination had a prevalence of 11.7% and yielded the highest estimated positive predictive value (PPV) (50.0 [95% CI: 34.2, 66.7]) and likelihood ratio positive (LR+) (5.2 [95% CI: 2.9, 9.7]). In late-stage OA knees, exam findings and symptoms provided minimal information beyond the prevalence. Patient report of both symptoms, or at least one positive exam finding and at least one symptom, could be used to identify knees at increased risk of effusion-synovitis in knees with early stage OA, either for screening purposes in clinical evaluation, or for study sample enrichment with an inflammatory phenotype; diagnostic performance was not sufficiently high for clinical diagnostic purposes.

Bone marrow lesion is associated with disability for activities of daily living in patients with early stage knee osteoarthritis.

Osteoarthritis of the knee (knee OA) induces pain, loss of mobility and diminished activities of daily living (ADL). Although an understanding of the pathophysiology of early stage knee OA has been developed, the structural changes associated with disability for ADL in early stage knee OA are still unclear. The aim of the present study was to examine magnetic resonance imaging (MRI)-detected changes associated with disability for ADL in patients with early stage knee OA. One hundred and thirty-two patients with early stage medial knee OA (Kellgren-Lawrence grade ≤ 2) who first visited the outpatient clinic at our university hospital were included. They were also examined by 3.0-Tesla knee MRI. The OA-associated structural changes were scored using the Whole-Organ Magnetic Resonance Imaging Score (WORMS), and clinical manifestations were evaluated by the Japanese Knee Osteoarthritis Measure (JKOM). Median quartile regression was used for the analysis. Cartilage lesion, subchondral bone attrition and osteophytes were observed in all patients. Bone marrow lesions (BMLs) and synovitis were observed in 60% and 55% of the patients, respectively. Subchondral cysts and ligament changes were observed in 6% and 17% of the patients, respectively. Pain severity of the patients was associated with medial cartilage lesions (coefficient 2.50, 95% confidence interval 0.61-4.40, p < 0.01). Disability for ADL of the patients was associated with BMLs in the medial side of the knee joint (0.82, 0.21-1.02, p = 0.04). BMLs in the medial side of the knee joint were associated with disability for ADL of patients with early stage medial knee OA.

Advances in the role of the infrapatellar fat pad in the initiation and progression of knee osteoarthritis

Osteoarthritis (OA) is a common chronic debilitating disease among middle-aged and old people, which can occur in the hip, knee, ankle, spine and other joints, but it is most commonly seen in the knee. The clinical manifestations of the knee osteoarthritis (KOA) include pain, swelling, stiffness, joint deformity, seriously affectting the quality of life. Mechanical and metabolic factors have been shown to play roles in the initiation and progression of this disease, resulting in a slow, progressive pathological process, and the normal balance of anabolic and catabolic activities of the chondrocytes has been disrupted. The mechanical factors are the joint imbalance caused by cartilage degeneration and ligament damage, and biochemical factors are mainly the changes of the joint microenvironment caused by the dysregulation of chondrocytes and synovitis. Infrapatellar fat pad (IPFP) is situated in the lower part of patella and femoral condyle, between tibia condyle and the patellar ligament, and it is an intracapsular but extrasynovial elastic fiber adipose tissue. Researches have shown that besides the synovial membrane, ligament, cartilage and bone, IPFP may play an important role in the onset and progression of KOA and knee pain. IPFP has long been regarded as a structural fatty tissue without metabolic reactions, thus often been neglected, what's more, to get a clear vision in knee surgery, IPFP is often partially or totally resected, but recently owning to its potential biological mechanics, endocrine function, which can produce a variety of inflammatory cytokines, chemokines, rich in nerve fiber structure and IPFP-adipose derived stem cells, more and more scholars pay attention to the IPFP. IPFP may play a protective role in the early stage of KOA by cushioning shock, stabilizing lubrication, but this article emphatically explain how IPFP play a desctructive role in the initiation and progression of KOA through leptin, adiponectin, and many other adipocytokines, or inflammatory mediators, so as to get further understanding of KOA, and discuss whether IPFP should be resected or not in knee surgery, providing a new method to the prevention and treatment of KOA.

New insights into the natural course of knee osteoarthritis: early regulation of cytokines and growth factors, with emphasis on sex-dependent angiogenesis and tissue remodeling. A pilot study

This study was conducted to identify cytokine profiles associated with radiographic phenotypes of knee osteoarthritis (rKOA) with a focus on early stage of the disease. The pilot population study involved 60 middle-aged patients (mean age 50±7.3y.). Standardized weight-bearing anteroposterior and axial radiographs were used to assess rKOA severity in tibiofemoral (TFJ) of patellofemoral joint (PFJ) by grading system (grades 0-3). Luminex (xMAP®) technology was used to simultaneously assess 60 biomarkers (BMs). Several pathways of angiogenic (CXCL10/IP-10, FGF1/2, PDGF-AA/BB, ANG1, RANTES), tissue remodeling/fibrosis (MMP1/3, TIMP2/3/4, TGFβ), and fat tissue (leptin) BMs associated with rKOA severity already in very early phase (grade 1). We identified several sets of cytokines as key markers of early knee osteoarthritis (KOA) predicting radiographic features in logistic-regression models (AUC=0.80-0.97). Marked sex-specificity of rKOA course was detected: upregulation of angiogenesis dominated in females, whereas the activation of tissue remodeling was dominant in males. Several of these shifts, e.g., decrease of CXCL10/IP-10, took place only in grade 1 KOA and disappeared or reversed in later stages. OA of different knee-joint compartments has distinct profiles of cytokines. A broad list of BMs (TIMP2/3/4, MMP1/3, TGFβ1/2, vWF-A2, sE-selectin and leptin) associated with OA in the PFJ. Our results demonstrate that substantial and time-limited shifts in the angiogenic and TIMP/MMP systems occur in the early stage of KOA. Our study findings highlight the sex-, grade- and compartment-dependent shifts in above processes. The data may contribute to the individualized prevention of KOA in the future.

Serum hyaluronan levels are associated with disability for activity of daily living in patients with knee osteoarthritis regardless of the radiographic severity of the disease

Purpose: Osteoarthritis (OA) is an age-related progressive joint disease, which is primarily characterized by cartilage degradation. OA of the knee is one of the major causes of morbidity and disability for activity of daily living (ADL) especially for elderly. Although plain radiographs are commonly used to detect OA in the clinical practice, it is hard to detect the essentials of the disease using plain radiographs. Biomarkers have characteristics which can be objectively measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions. Biomarkers have been developed to aid for diagnosing early-stage knee OA, predicting OA progression, and assessing therapeutic response. The availability of biomarkers, in addition to imaging technologies, e.g. magnetic resonance imaging (MRI), could dramatically improve diagnosis and treatment of OA. Hyaluronic acid and interleukin-6 in serum (sHA and sIL-6, respectively) are the potential candidates for biomarkers in knee OA. sHA was shown to be associated with pain of the patients with knee OA. sHA and sIL-6 were also shown to be predictors for the radiographic progression of knee OA. We also reported that sHA levels were associated with the severity of knee OA (BMC Musculoskelet Disord 2013) and sIL-6 levels were associated with pain (Osteoarthritis Cartilage 2013) and depressive state (Clin Rheum 2017) of the patients with knee OA. However, it has not been examined that whether sHA and sIL-6 were associated with disability for ADL in patients with knee OA. In this study, we examined the associations between sHA as well as sIL-6 levels and disability for ADL in patients with knee OA. Methods: One-hundred and fifteen postmenopausal women who attended our clinic with a main complaint of knee pain, showed radiographic knee OA (Kellgren-Lawrence [K/L] grade ≥2) and provided informed consent to participate in this study were enrolled. Patients with a history of hepatic diseases were excluded. The subjects were divided into two groups according to the radiographic severity of the disease: early stage group (K/L grade 2) and advanced stage group (K/L grades 3/4). Correlations between the subcategory of ADL of the Japanese Knee Osteoarthritis Measure (JKOM) or pain visual analog scale (VAS) and sHA or sIL-6 were calculated using Pearson's correlation coefficient. Results: When all the patients (early- and advanced-groups) were included, ADL was correlated with pain VAS of the patients (r = 0.58, P < 0.01). sHA was correlated with sIL-6 of all the patients (r = 0.26, P = 0.01). Disability of ADL was correlated with both sHA (r = 0.31, P < 0.01) and sIL-6 (r = 0.33, P < 0.01) of all the patients. Pain VAS was also correlated with both sHA (r = 0.26, P < 0.01) and sIL-6 (r = 0.25, P = 0.01) of all the patients. In the early stage knee OA group, ADL was also correlated with pain VAS of the patients (r = 0.53, P < 0.01). However, sHA was not correlated with sIL-6 of the early stage knee OA patients (r = 0.08, P = 0.56). Disability of ADL was correlated with both sHA (r = 0.50, P < 0.01) and sIL-6 (r = 0.30, P = 0.03) of the early stage knee OA patients. Pain VAS was correlated with sIL-6 (r = 0.31, P = 0.02) of the early stage knee OA patients, while it was not correlated with sHA (r = 0.27, P = 0.06). In the advanced stage knee OA group, ADL was also correlated with pain VAS of the patients (r = 0.64, P < 0.01). sHA was correlated with sIL-6 of the advanced knee OA patients (r = 0.31, P = 0.01). Disability of ADL was correlated with sHA of the advanced knee OA patients (r = 0.32, P = 0.01), while it was not correlated with sIL-6 (r = 0.20, P = 0.12). Pain VAS was also correlated with sHA (r = 0.31, P = 0.01), but not with sIL-6 (r = 0.19, P = 0.14), of the advanced knee OA patients. Conclusions: sHA is considered to be associated with synovitis in patients with knee OA. In our previous study, synovitis detected by the non-enhanced MRI was associated with both disability of ADL and subchondral bone pathologies detected by MRI of the patients with end stage knee OA (Osteoarthritis Cartilage 2015). Although further study is needed, the association between sHA, synovitis and subchondral bone pathologies detected by MRI is suggested in patients with knee OA.In conclusion, sHA was correlated with disability of ADL in patients with knee OA regardless of the radiographic severity of the disease.