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Meniscus pathologies (damage, extrusion) and synovitis are associated with knee osteoarthritis (KOA); however, whether synovitis mediates the relationship between meniscus pathologies and KOA radiographic progression remains unclear. We conducted an observational study in the Osteoarthritis Initiative (OAI) cohort, with a 48-month follow-up. Meniscus pathology and synovitis were measured by MRI osteoarthritis knee score (MOAKS) at baseline and 24 months, and a comprehensive synovitis score was calculated using effusion and Hoffa synovitis scores. The knee osteoarthritis radiographic progression was considered that Kellgren-Lawrence (KL) grade and joint space narrowing (JSN) grade at 48 months were increased compared to those at baseline. This study included a total of 589 participants, with KL grades mainly being KL1 (26.5%), KL2 (34.1%), and KL3 (30.2%) at baseline, while JSN grades were mostly 0 at baseline. A logistic regression model was used to analyze the relationship between meniscus pathology, synovitis, and KOA progression. Mediation analysis was used to evaluate the mediation effect of synovitis. The average age of the participants was 61 years old, 62% of which were female. The medial meniscus extrusion was longitudinally correlated with the progression of KL (odds ratio [OR]: 2.271, 95% confidence interval [CI]: 1.412-3.694) and medial JSN (OR: 3.211, 95% CI: 2.040-5.054). Additionally, the longitudinal correlation between medial meniscus damage and progression of KOA (OR: 1.853, 95% CI: 1.177-2.941) and medial JSN (OR: 1.655, 95% CI: 1.053-2.602) was significant. Synovitis was found to mediate the relationship between medial meniscus extrusion and KL and medial JSN progression at baseline (ß: 0.029, 95% CI: 0.010-0.053; ß: 0.022, 95% CI: 0.005-0.046) and beyond 24 months (ß: 0.039, 95% CI: 0.016-0.068; ß: 0.047, 95% CI: 0.020-0.078). However, we did not find evidence of synovitis mediating the relationship between meniscal damage and KOA progression. Synovitis mediates the relationship between medial meniscus extrusion (rather than meniscus damage) and KOA progression.

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Osteoarthritis (OA) progresses due to the excessive generation of reactive oxygen and nitrogen species (ROS/RNS) and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria. Highly active single-atom nanozymes (SAzymes) can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases. In this study, we innovatively utilised ligand-mediated strategies to chelate Pt4+ with modified g-C3N4 by π-π interaction to prepare g-C3N4-loaded Pt single-atom (Pt SA/C3N4) nanozymes that serve as superoxide dismutase (SOD)/catalase (CAT) mimics to scavenge ROS/RNS and regulate mitochondrial ATP production, ultimately delaying the progression of OA. Pt SA/C3N4 exhibited a high loading of Pt single atoms (2.45 wt%), with an excellent photothermal conversion efficiency (54.71%), resulting in tunable catalytic activities under near-infrared light (NIR) irradiation. Interestingly, the Pt-N6 active centres in Pt SA/C3N4 formed electron capture sites for electron holes, in which g-C3N4 regulated the d-band centre of Pt, and the N-rich sites transferred electrons to Pt, leading to the enhanced adsorption of free radicals and thus higher SOD- and CAT-like activities compared with pure g-C3N4 and g-C3N4-loaded Pt nanoparticles (Pt NPs/C3N4). Based on the use of H2O2-induced chondrocytes to simulate ROS-injured cartilage invitro and an OA joint model invivo, the results showed that Pt SA/C3N4 could reduce oxidative stress-induced damage, protect mitochondrial function, inhibit inflammation progression, and rebuild the OA microenvironment, thereby delaying the progression of OA. In particular, under NIR light irradiation, Pt SA/C3N4 could help reverse the oxidative stress-induced joint cartilage damage, bringing it closer to the state of the normal cartilage. Mechanistically, Pt SA/C3N4 regulated the expression of mitochondrial respiratory chain complexes, mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase, to reduce ROS/RNS and promote ATP production. This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.

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Imaging biomarkers permit improved approaches to identify the most at-risk patients encountering knee osteoarthritis (KOA) progression. This study aimed to investigate the utility of trabecular bone texture (TBT) extracted from plain radiographs, associated with a set of clinical, biochemical, and radiographic data, as a predictor of long-term radiographic KOA progression. We used data from the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium dataset. The reference model made use of baseline TBT parameters adjusted for clinical covariates and radiological scores. Several models based on a combination of baseline and 24-month TBT variations (TBT∆TBT) were developed using logistic regression and compared to those based on baseline-only TBT parameters. All models were adjusted for baseline clinical covariates, radiological scores, and biochemical descriptors. The best overall performances for the prediction of radio-symptomatic, radiographic, and symptomatic progression were achieved using TBT∆TBT parameters solely, with area under the ROC curve values of 0.658 (95% CI: 0.612-0.705), 0.752 (95% CI: 0.700-0.804), and 0.698 (95% CI: 0.641-0.756), respectively. Adding biochemical markers did not significantly improve the performance of the TBT∆TBT-based model. Additionally, when TBT values were taken from the entire subchondral bone rather than just the medial, lateral, or central compartments, better results were obtained.

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PURPOSE: To analyze the association between change in knee joint line obliquity (KJLO) and patient-reported outcome, radiological progression of osteoarthritis, and surgical survival after lateral closing-wedge high tibial osteotomy (HTO). METHODS: A cohort of 180 patients treated in one single hospital with lateral closing-wedge HTO was examined. KJLO was defined by the medial proximal tibial angle (MPTA). To assess the association between KJLO and patient-reported outcome, radiological progression of osteoarthritis, and surgical survival, patient groups were defined: I, postoperative MPTA < 95.0°; II, postoperative MPTA ≥ 95.0°; A, MPTA change < 8.0°; B, MPTA change ≥ 8.0°. Propensity score matching was used for between-groups (I and II, A and B) covariates matching, including age, gender, preoperative lower limb alignment, preoperative medial joint space width (mJSW), preoperative Western Ontario and McMaster Universities osteoarthritis Index (WOMAC) score, wedge size, and postoperative follow-up time. Patient-reported outcome was assessed by the WOMAC questionnaire, radiological progression of osteoarthritis by mJSW and Kellgren-Lawrence (KL) grade progression (≥ 1) preoperatively and at follow-ups (> 2 years). Failure was defined as revision HTO or conversion to knee arthroplasty. RESULTS: After propensity score matching, groups I and II contained 58 pairs of patients and groups A and B contained 50 pairs. There were no significant differences in postoperative WOMAC score or surgical failure rate between groups I and II or between groups A and B (p > 0.05). However, the postoperative mJSW was significantly lower in group I than group II (3.2 ± 1.6 mm vs 3.9 ± 1.8 mm; p = 0.018) and in group A than group B (3.0 ± 1.7 mm vs 3.7 ± 1.5 mm; p = 0.040). KL grade progression rate was significantly higher in group I than group II (53.4% vs 29.3%; p = 0.008) and in group A than group B (56.0% vs 28.0%; p = 0.005). CONCLUSION: Increased KJLO (postoperative MPTA ≥ 95.0°) or MPTA change ≥ 8.0° after lateral closing-wedge HTO does not adversely affect patient-reported outcome, radiological progression of osteoarthritis, or surgical survival at an average 5-year follow-up. LEVEL OF EVIDENCE: III, retrospective cohort study.

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Changes in clinical presentation, radiographic progression (RP), bone mineral density (BMD), bone turnover (BT), and cartilage turnover (CT) markers were compared in two groups of patients with hip osteoarthritis (HOA) over a period of 7 years. Each group consisted of 150 patients, including a control group on standard-of-care therapy (SC) with simple analgesics and physical exercises, and a study group (SG) on standard-of-care therapy supplemented by vitamin D3 and intravenous administration of zoledronic acid (5 mg) yearly for 3 consecutive years. Patient groups were homogenized regarding the following: (1) radiographic grade (RG), including 75 patients with hip OA RG II according to the Kellgren-Lawrence grading system (K/L), and 75 with RG III on K/L; (2) radiographic model (RM), as each of the K/L grades was subdivided into three subgroups consisting of 25 patients of different RMs: atrophic ('A'), intermediate ('I'), and hypertrophic ('H'); (3) gender-equal ratio of men and women in each subgroup (Female/Male = 15/10). The following parameters were assessed: (1) clinical parameters (CP), pain at walking (WP-VAS 100 mm), functional ability (WOMAC-C), and time to total hip replacement (tTHR); (2) radiographic indicators(RI)-joint space width (JSW) and speed of joint space narrowing (JSN), changes in BMD (DXA), including proximal femur (PF-BMD), lumbar spine (LS-BMD), and total body (TB-BMD); (3) laboratory parameters (LP)-vitamin D3 levels and levels of BT/CT markers. RV were assessed every 12 months, whereas CV/LV were assessed every 6 months. Results: Cross-sectional analysis (CsA) at baseline showed statistically significant differences (SSD) at p < 0.05 in CP (WP, WOMAC-C); BMD of all sites and levels of CT/BT markers between the 'A' and 'H' RM groups in all patients. Longitudinal analysis (LtA) showed SSD (p < 0.05) between CG and SG in all CP (WP, WOMAC-C, tTHR) parameters of RP (mJSW, JSN), BMD of all sites, and levels of CT/BT markers for all 'A' models and in 30% of 'I'-RMs (those with elevated markers for BT/CT at baseline and during the observation period). Conclusion: The presence of SSD at baseline ('A' vs. 'H') supported the thesis that at least two different subgroups of HOA exist: one associated with 'A' and the other with 'H' models. D3 supplementation and the intravenous administration of bisphosphonate were the treatment strategies that slowed down RP and postponed tTHR by over 12 months in the 'A' and 'I' RM with elevated BT/CT markers.

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BACKGROUND: Synovial inflammation is a risk factor for osteoarthritis (OA). But to date, there is limited information on how inflammation impacts progression of knee OA. PURPOSE: To investigate how sustained synovitis, assessed with semi-quantitative magnetic resonance imaging (MRI) scores, impacts progression of knee degenerative changes over 4 years. STUDY TYPE: Retrospective cohort study. SUBJECTS: In 249 participants (N = 132 women [53%]), from the Osteoarthritis Initiative (OAI) two definitions for synovitis were used resulting in two groups of participants with sustained synovitis at baseline, 2-year, and 4-year follow-up (N = 80 and N = 132), and two groups without synovitis at all three time points (N = 81 and N = 47). FIELD STRENGTH/SEQUENCE: 3 T intermediate-weighted (IW) turbo spin-echo (TSE) sequence and three-dimensional (3D) dual-echo steady-state (DESS) sequence. ASSESSMENT: Synovitis was scored semi-quantitatively using the Anterior Cruciate Ligament Osteoarthritis Score (ACLOAS), MRI Osteoarthritis Knee Score (MOAKS), and synovial proliferation score (SPS). Two MRI-based definitions of synovitis were used: (i) score ≥2 based on cumulative score of MOAKS and ACLOAS, and (ii) score ≥3 based on the cumulative score of ACLOAS, MOAKS, and SPS. Changes in structural abnormalities from baseline to year 4 measured using the whole-organ MRI score (WORMS) were defined as outcomes. STATISTICAL TESTS: Linear regression models were used to compare the differences in longitudinal changes in WORMS scores between participants with and without sustained synovitis for each definition of sustained synovitis. A P-value of <0.05 was considered statistically significant. RESULTS: Significantly higher rates of progression were found in participants with synovitis for patellar (Beta coeff. = 0.29) and medial tibial cartilage abnormalities (Beta coeff. = 0.29) for definition (i). For definition (ii), patellar (Beta coeff. = 0.36) and medial femoral cartilage (Beta coeff. = 0.30) abnormalities demonstrated significant differences. DATA CONCLUSION: Greater progression of structural degenerative disease was observed in individuals with sustained synovitis compared to those without sustained synovitis, suggesting that sustained synovitis is associated with progressive OA. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

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BACKGROUND: Although eccentric acetabular rotation osteotomy (ERAO) is an effective treatment for developmental dysplasia of the hip (DDH), there is little information about return to sports after ERAO. This study aimed to investigate 1) the patient factors that influence the return to sports after ERAO, 2) whether postoperative sports participation will affect future osteoarthritis progression. HYPOTHESIS: Some factors affect the return to sports after ERAO. PATIENTS AND METHODS: Of 503 patients who underwent ERAO from 1990 to 2010, 124 who had been continuously participating in sports preoperatively (average 13.2 years after surgery) were included. Patient demographics of sex, age, body mass index, unilateral to bilateral case ratio, history of treatment for childhood DDH, preoperative Kellgren-Lawrence (KL) grade, center edge angle, joint congruency, Harris hip score, complications and the survival rate were compared between the S group (patients who participated in the same sports preoperatively) and N group (patients who could not participate in sports postoperatively). RESULTS: Seventy-two (58%) and 52 patients (42%) in the S and N groups, respectively, had an overall return to sports rate of 64% (79 patients). The most common sports that patients participated in were swimming (30 patients [24%]), jogging (12 [10%]), and golf (10 [8%]) preoperatively, and swimming (14 patients [11%]), golf (8 [6%]), and jogging (8 [6%]) postoperatively. There were no significant differences between both groups in terms of sex, age, body mass index, unilateral to bilateral case ratio, history of treatment for childhood DDH, preoperative KL grade, and joint congruency. There was a significant difference in patient factors between the S (11 joints [14%]) and N (20 joints [38%]) groups only when the preoperative center edge angle was <0°. There was no significant difference in the preoperative Harris hip score and the final survey between the S (73.2±4.6 and 93.4±7.2) and N (72.5±4.8 and 92.1±7.4) groups. Complications showed no significant differences between the five patients (7%) in the S group and six patients (13%) in the N group. The KL grade progressed in 10 cases (grade II to III in 2 cases and grade III to IV in 8) in the S group and 8 cases (grade II to III in 1 case and grade III to IV in 7 cases) in the N group. The 10-year and 20-year joint survival rates with THA conversion as the endpoint were 98.1% (95% CI: 87.4%-99.7%) and 83.7% (95% CI: 62.6%-93.4%) in the S group and 100% (95% CI: 70.7%-99.3%) and 95.2% (95% CI: 12.6%-92.6%) in the N group, respectively. In the evaluation of factors affecting sports return by logistic regression analysis, only one significant factor (odds ratio 3.42, 95% confidence interval: 1.58-7.42, p<0.01) was the preoperative center edge angle <0°. DISCUSSION: The chief factor affecting the return to sports after surgery was a preoperative center edge angle <0°; moreover, the continuation of sports did not affect the subsequent progression of osteoarthritis or THA conversion. LEVEL OF EVIDENCE: level III, cohort study.

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PURPOSE: The aim of this study is to compare the functional outcomes and osteoarthritis (OA) progression after anterior cruciate ligament (ACL) reconstruction with either hamstring autografts or allografts in people over 50. METHODS: The clinical records of two consecutive cohorts of 61 cases in total over 50 years of age, undergoing ACL reconstruction, were included. The first cohort consisted of 29 allografts; the second cohort consisted of 32 autologous hamstring tendon grafts. The cases were evaluated pre- (T0) and post-operatively at six months (T1), 12 months (T2) and 24 months (T3). Clinical examination included the Lachman test, pivot shift test and objective (Objective IKDC [The International Knee Documentation Committee] score) and subjective clinical scores (Subjective IKDC score, Lysholm score and Tegner activity score). The degree of OA was evaluated using the Kellgren-Lawrence system at the time of the final follow-up, compared to the pre-operative condition. RESULTS: No pre-operative difference was found between the two groups (p > 0.05). No statistical difference was noted between the two groups at each follow-up (p > 0.05). At the final follow-up, both the groups significantly improved statistically in all the clinical and functional scores (p < 0.05). In both groups, one graft re-rupture was noted. No progression of OA was noted in both groups at final follow-up (p > 0.05). CONCLUSION: The graft choice does not influence the outcomes two years after ACL reconstruction in people over 50; thus, both treatments help in regaining knee stability with no signs of OA progression. REGISTRATION: Researchregistry7539- www.researchregistry.com .

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Objectives: To identify plasma extracellular vesicles (EVs) associated with radiographic knee osteoarthritis (OA) progression. Methods: EVs of small (SEV), medium (MEV) and large (LEV) sizes from plasma of OA participants (n=30) and healthy controls (HCs, n=22) were profiled for surface markers and cytokine cargo by high-resolution flow cytometry. The concentrations of cytokines within (endo-) and outside (exo-) EVs were quantified by multiplex ELISA. EV associations with knee radiographic OA (rOA) progression were assessed by multivariable linear regression (adjusted for baseline clinical variables of age, gender, BMI and OA severity) and receiver operating characteristic (ROC) curve analysis. Results: Based on integrated mean fluorescence intensity (iMFI), baseline plasma MEVs carrying CD56 (corresponding to natural killer cells) predicted rOA progression with highest area under the ROC curve (AUC) 0.714 among surface markers. Baseline iMFI of TNF-α in LEVs, MEVs and SEVs, and the total endo-EV TNF-α concentration, predicted rOA progression with AUCs 0.688, 0.821, 0.821, 0.665, respectively. In contrast, baseline plasma exo-EV TNF-α (the concentration in the same unit of plasma after EV depletion) did not predict rOA progression (AUC 0.478). Baseline endo-EV IFN-γ and exo-EV IL-6 concentrations were also associated with rOA progression, but had low discriminant capacity (AUCs 0.558 and 0.518, respectively). Conclusions: Plasma EVs carry pro-inflammatory cargo that predict risk of knee rOA progression. These findings suggest that EV-associated TNF-α may be pathogenic in OA. The sequestration of pathogenic TNF-α within EVs may provide an explanation for the lack of success of systemic TNF-α inhibitors in OA trials to date.

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BACKGROUND & OBJECTIVES: Decorin is a proteoglycan that plays a role in the binding of collagen and has an important role in the pathogenesis of osteoarthritis (OA). This study was aimed to determine serum and synovial fluid decorin levels in patients with knee OA and to investigate whether these levels were associated with OA and the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) score. METHODS: In this prospective study 88 participants were included (44 knee OA and 44 with other knee joint diseases) in the study and control groups. Knee function was assessed using the WOMAC score. The serum and synovial fluid decorin levels were analyzed using a human decorin ELISA. Binary logistic regression with a single and multi-categorical predictor was used to determine the possible risk factors for OA. RESULTS: The serum decorin levels were significantly higher in the OA group than the control group (P<0.002).s The synovial fluid decorin levels were not significantly different between OA and control groups. WOMAC score [odds ratio (OR)=1.073, 95% confidence interval (CI): 1.032-1.116, P<0.001] and high serum decorin levels (OR=1.114, 95%CI: 1.030-1.205, P=0.007) were found to be significant in the determination of OA. Serum decorin levels were positively correlated with the WOMAC score in OA. INTERPRETATION & CONCLUSIONS: An increased serum decorin levels may be indicative of changes in extracellular matrix structure. The positive correlation between serum decorin level and WOMAC score supports this result. Increased serum decorin levels and WOMAC score were found to be risk factors associated with OA. However, the decorin level in the joint fluid was not associated with OA.

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BACKGROUND: While some individual foods and nutrients have been associated with knee osteoarthritis (KOA) progression, the association between dietary patterns and KOA progression has received little research attention. OBJECTIVE: The objective of this study was to determine whether dietary patterns, derived by principal components analysis (PCA), are associated with KOA progression. METHODS: In the Osteoarthritis Initiative (OAI), a prospective cohort with clinical centers in Maryland, Ohio, Pennsylvania, and Rhode Island, 2757 participants with existing KOA (mean age 62 y) and diet assessed at baseline were followed for ≤72 mo. Using PCA, Western and prudent dietary patterns were derived. Radiographic KOA progression was assessed using 2 separate measures, 1 full Kellgren-Lawrence (KL) grade increase and loss in joint space width (JSW). Symptomatic KOA progression was defined as an increase in or remaining in 1 of the 2 highest classification categories of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). RESULTS: Adherence to Western and prudent dietary patterns was significantly associated with radiographic and symptomatic progression of KOA. With increasing Western pattern score, there was increased KL-worsening risk (compared with quartile 1, HR for quartile 4: 1.30; 95% CI: 1.05, 1.61; P-trend < 0.01) and increased odds of progression to higher WOMAC score (compared with quartile 1, OR for quartile 4: 1.39; 95% CI: 1.18, 1.63; P-trend < 0.01) but no significant change in JSW loss. With increasing prudent pattern score there was decreased KL-worsening risk (compared with quartile 1, HR for quartile 4: 0.79; 95% CI: 0.64, 0.98; P-trend = 0.02), decreased JSW loss (quartile 1: 0.46 mm; quartile 4: 0.38 mm; P-trend < 0.01), and decreased odds of higher WOMAC progression (compared with quartile 1, OR for quartile 4 0.73; 95% CI: 0.62, 0.86; P-trend < 0.01) in multivariable adjusted models. CONCLUSIONS: Adherence to a Western dietary pattern was associated with increased radiographic and symptomatic KOA progression, while following a prudent pattern was associated with reduced progression. In general, for people already diagnosed with KOA, eating a diet rich in fruits, vegetables, fish, whole grains, and legumes may be related to decreased radiographic and symptomatic disease progression.

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OBJECTIVE: The aim of this study was to document the natural history of development and long-term progression of osteoarthritis (OA) in the feline knee after minimally invasive anterior cruciate ligament (ACL) transection. DESIGN: ACL transections of the left knee joint of 14 skeletally mature cats were performed. Radiographic scores, tibiofemoral and patellofemoral joint space and anterior tibial translation were assessed before, immediately and every 3 months after ACL transection (longest follow-up: 93 months). RESULTS: After 26 months, all ACL transected knees had developed definite OA. The earliest changes were observed on the tibia plateau starting as early as 2 months after ACL transection, and at 12 months signs of OA were present in more than 80% of cats in the medial and in almost 80% of cats in the lateral compartment. In the first 24 months, medial tibiofemoral joint space decreased by 0.88 mm (95% confidence interval [-0.55;-1.21] mm) and lateral tibiofemoral joint space by 0.55 mm ([-0.26;-0.85] mm). In the same interval, the joint space in the patellofemoral joint increased by 0.98 mm ([0.59; 1.37] mm). Throughout the entire observation period, the anterior tibial translation was on average 5.3 mm greater than in the contralateral knee ([4.5; 6.0]mm). CONCLUSIONS: Immediate changes in anterior tibial translation during an anterior drawer test clearly showed joint instability that persisted throughout the lifetime of the animals. Degenerative changes were observed on radiographs within 4 months of the injury only in the transected but not the contralateral limb suggesting the role of mechanical instability for the development and progression of knee OA.

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The purpose of this study is to determine whether full-thickness tibiofemoral cartilage defects are predictive of incident radiographic OA, progression of radiographic OA, and progression to severe radiographic OA. Participants in the OA Initiative (n = 1317, 38.1% male, mean age 60.9 years SD 9.2) with baseline MRIs and Kellgren-Lawrence (KL) OA grade 0-3 (none to moderate OA) were included. All participants had follow-up radiographs at mean 4.9 years (max 8.0). The effect of full-thickness defect presence, size, and location on risk of incident OA (KL grade 2+), overall progression of OA (increase in KL grade 1+ points), or compartment-specific OA progression was assessed with Cox proportional hazards modeling with adjustment for demographic factors, weight, and knee alignment. The yearly incidence of tibiofemoral OA was 0.3% (CI 0.2-0.4%); defect presence, size, and location were not associated with incident OA risk. The yearly rate of OA progression was 3.8% in participants without tibiofemoral full-thickness defects, 6.7% with medial defects, and 6.3% with lateral defects. Medial bipolar (kissing) lesions were an independent risk factor for OA progression as well as medial compartment progression. Lateral tibial-sided full-thickness defects increased risk of lateral progression (increase in lateral OARSI grade). In older adults, isolated full-thickness cartilage defects do not increase short-term risk of incident OA. However, in the setting of preexisting mild or moderate OA, medial bipolar (kissing) defects increase risk of overall OA progression (KL grade) as well as progression of medial compartment OA. Lateral tibial defects increase risk of lateral compartment OA progression. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

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OBJECTIVES: In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models. METHODS: OA was induced in the knee joints of male Wistar rats using transection of the ACL or induction of osteochondral injury. Changes in the percentage of high limb weight distribution (%HLWD) on the operated hind limb were used to determine the pain behaviour in these models. The development of OA was assessed and compared using a histological evaluation based on the Osteoarthritis Research Society International (OARSI) cartilage OA histopathology score. RESULTS: Both models showed an increase in joint pain as indicated by a significant (p < 0.05) decrease in the values of %HLWD at one week post-surgery. In the osteochondral injury model, the %HLWD returned to normal within three weeks, while in the ACLT model, a significant decrease in the %HLWD was persistent over an eight-week period. In addition, OA progression was more advanced in the ACLT model than in the osteochondral injury model. Furthermore, the ACLT model exhibited a higher mean OA score than that of the osteochondral injury model at 12 weeks. CONCLUSION: The development of pain patterns in the ACLT and osteochondral injury models is different in that the OA progression was significant in the ACLT model. Although both can be used as models for a post-traumatic injury of the knee, the selection of appropriate models for OA in preclinical studies should be specified and relevant to the clinical scenario.Cite this article: T. Tawonsawatruk, O. Sriwatananukulkit, W. Himakhun, W. Hemstapat. Comparison of pain behaviour and osteoarthritis progression between anterior cruciate ligament transection and osteochondral injury in rat models. Bone Joint Res 2018;7:244-251. DOI: 10.1302/2046-3758.73.BJR-2017-0121.R2.

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PURPOSE: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. METHODS: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1ß or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays. RESULTS: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. CONCLUSIONS: TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.

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OBJECTIVES: To determine the association between the long-term use of analgesics and progression of osteoarthritis (OA) as evidenced by up to 3-years follow-up worsening of radiographic Kellgren-Lawrence (KL) grade and incidence of knee replacement (KR). DESIGN: Using nearest neighbor matching of the propensity scores with caliper in the Osteoarthritis Initiative (OAI) cohort, 173 index (Analgesic +) and 173 referent (Analgesic -) subjects were included. Analgesic + and - subjects had analgesics in all and none of their visits, respectively. Analgesic + and - subjects were balanced in their demographics, baseline, first, second and third year body mass index (BMI), Western Ontario and McMaster (WOMAC) total score, Physical and Mental health summary scales (SF-12), Physical Activity Scale for the Elderly (PASE) and Charleston Comorbidity Scale. Analgesic + and - subjects were also matched for baseline radiographic KL grade. Interval increase in the KL grade and incidence of KR were defined as the outcome. RESULTS: Included subjects had average 6.5 years of follow-up. By the third year, 44 subjects had an interval increase in the KL grade; 29 in Analgesic + and 15 among Analgesic - subjects (P = 0.024). By the eighth-year, 41 subjects had their first KR; 29 in Analgesic + and 12 among Analgesic - subjects (P = 0.005). Hazard Ratio (HR) of OA progression and KR for Analgesic + subjects was 1.91 (1.02-3.57) and 2.57 (1.31-5.04), respectively. CONCLUSIONS: Long-term use of analgesics may be associated with radiographic progression of knee OA and increased risk of future KR.

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OBJECTIVE: To identify disease relevant genes and pathways associated with knee Osteoarthritis (OA) progression in human subjects using medial and lateral compartment dominant OA knee tissue. DESIGN: Gene expression of knee cartilage was comprehensively assessed for three regions of interest from human medial dominant OA (n = 10) and non-OA (n = 6) specimens. Histology and gene expression were compared for the regions with minimal degeneration, moderate degeneration and significant degeneration. Agilent whole-genome microarray was performed and data were analyzed using Agilent GeneSpring GX11.5. Significant differentially regulated genes were further investigated by Ingenuity Pathway Analysis (IPA) to identify functional categories. To confirm their association with disease severity as opposed to site within the knee, 30 differentially expressed genes, identified by microarray, were analyzed by quantitative reverse-transcription polymerase chain reaction on additional medial (n = 16) and lateral (n = 10) compartment dominant knee OA samples. RESULTS: A total of 767 genes were differentially expressed ≥ two-fold (P ≤ 0.05) in lesion compared to relatively intact regions. Analysis of these data by IPA predicted biological functions related to an imbalance of anabolism and catabolism of cartilage matrix components. Up-regulated expression of IL11, POSTN, TNFAIP6, and down-regulated expression of CHRDL2, MATN4, SPOCK3, VIT, PDE3B were significantly associated with OA progression and validated in both medial and lateral compartment dominant OA samples. CONCLUSIONS: Our study provides a strategy for identifying targets whose modification may have the potential to ameliorate pathological alternations and progression of disease in cartilage and to serve as biomarkers for identifying individuals susceptible to progression.

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OBJECTIVE: We investigated the relationship between the molecular weight (MW) distribution of hyaluronan (HA) in synovial fluid (SF) and risk of knee osteoarthritis (OA) progression. METHODS: HA MW was analyzed for 65 baseline knee SFs. At 3-year follow-up, knees were scored for change in joint space narrowing (JSN), osteophyte (OST) progression, or occurrence of total knee arthroplasty (TKA). HA MW distribution was analyzed using agarose gel electrophoresis (AGE), and its relationship to OA progression was evaluated using logistic regression. The association between HA MW and self-reported baseline knee pain was analyzed using Pearson's correlation coefficients. RESULTS: Knee OA was categorized as non-progressing (OST-/JSN-, 26 knees, 40%), or progressing based on OST (OST+/JSN-, 24 knees, 37%), OST and JSN (OST+/JSN+, 7 knees, 11%) or total knee arthroplasty (TKA, 8 knees, 12%). The MW distribution of HA in baseline SFs was significantly associated with the odds of OA progression, particularly for index knees. After adjusting for age, gender, BMI, baseline X-ray grade and pain, each increase of one percentage point in %HA below 1 million significantly increased the odds of JSN (odds ratios (OR) = 1.45, 95% CI 1.02-2.07), TKA or JSN (OR = 1.24, 95%CI 1.01-1.53) and the odds of any progression (OR = 1.16, 95% CI 1.01-1.32). HA MW distribution significantly correlated with pain. CONCLUSION: These data suggest that the odds of knee OA progression increases as HA MW distribution shifts lower and highlight the value of reporting MW distribution rather than just average MW values for HA.

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OBJECTIVE: To evaluate the role of three cartilage-derived biomarkers on osteoarthritis (OA): urinary C-terminal telopeptide (uCTX-II), serum cartilage oligomeric protein (sCOMP), and serum MMP degraded type II collagen (sC2M). SUBJECTS AND METHODS: Samples from 3582 individuals from the Rotterdam Study, the Genetics osteoArthritis and Progression (GARP), the Chingford Study and the TwinsUK cohort were assayed using enzyme-linked immune sorbent assays. Log10 of concentration levels were correlated with risk of hip, hand and knee OA, hip and knee OA severity and incidence, and progression of knee OA, adjusting for age, gender and body mass index (BMI). Results were meta-analysed to assess overall significance. RESULTS: After adjusting for covariates, sCOMP was associated with knee OA and hip and knee OA incidence. Furthermore, sC2M was associated with knee OA incidence and progression. After adjustment for multiple tests (Bonferroni P < 0.002) only the association between sCOMP and knee OA remained significant (odds ratio (OR) = 3.26 (95%CI 1.63-10.1) P = 0.0008 for each standard deviation (SD) increase in biomarker levels). Levels of uCTX-II were significantly associated with risk of hand, hip and knee OA, progression and incidence of knee OA. A receiver operating characteristics (ROC) analysis showed a consistent improvement in prediction of knee OA progression from an average area under the curve (AUC) is 0.646 for age, sex and BMI alone to an AUC = 0.668 including uCTX-II for prediction. CONCLUSIONS: uCTX-II is the most informative biochemical marker for prediction of OA. Both sCOMP and C2M showed some association with OA, thus indicating that they are descriptive of disease activity.

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The identification of new components implicated in the pathogenesis of osteoarthritis (OA) might improve our understanding of the disease process. Here, we investigated the levels of the survival of motor neuron (SMN) expression in OA cartilage considering the fundamental role of the SMN protein in cell survival and its involvement in other stress-associated pathologies. We report that SMN expression is up-regulated in human OA compared with normal cartilage, showing a strong correlation with the disease severity, a result confirmed in vivo in an experimental model of the disease. We further show that the prominent inflammatory cytokines (IL-1ß, TNF-α) are critical inducers of SMN expression. This is in marked contrast with the reported impaired levels of SMN in spinal muscular atrophy, a single inherited neuromuscular disorder characterized by mutations in the smn gene whereas OA is a complex disease with multiple aetiologies. While the precise functions of SMN during OA remain to be elucidated, the conclusions of this study shed light on a novel pathophysiological pathway involved in the progression of OA, potentially offering new targets for therapy.

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