Medial meniscus extrusion is invariably observed and consistent with tibial osteophyte width in elderly populations: The Bunkyo Health Study.

We reported that the full-length width of medial tibial osteophytes comprising cartilage and bone parts correlates with medial meniscus extrusion (MME) in early-stage knee osteoarthritis (OA). However, no data exist on the prevalence of MME and its relationship with osteophytes in the elderly population. 1191 elderly individuals (females 57%; 72.9 years old on average) in the Bunkyo Health Study underwent standing plain radiograph and proton density-weighted MRI on knee joints. MRI-detected OA changes were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. A new method of assessing the cartilage and bone parts of osteophytes was developed using pseudo-coloring images of proton density-weighted fat-suppressed MRI. Most subjects showed Kellgren-Lawrence grade 1 or 2 radiographic medial knee OA (88.1%), MME (98.7%, 3.90 ± 2.01 mm), and medial tibial osteophytes (99.3%, 3.27 ± 1.50 mm). Regarding OA changes, MME was closely associated with the full-length width of medial tibial osteophytes (ß = 1.114; 95% CI 1.069-1.159; p < 0.001) in line with osteophyte width (intraclass correlation coefficient, 0.804; 95% CI 0.783-0.823). Our data revealed that MME and medial tibial osteophytes are observed in the elderly and demonstrate that the degree of MME is consistent with the full-length width of medial tibial osteophytes, suggesting that osteophytes might be implicated in MME.

Anterior meniscus extrusion is associated with anterior tibial osteophyte width in knee osteoarthritis - The Bunkyo Health Study.

Background: In knee osteoarthritis (OA), medial meniscus extrudes both medially and anteriorly. We reported that full-length width of medial tibial osteophyte, which comprises cartilage and bone parts, is directly associated with medial meniscus extrusion in early-stage knee OA and hypothesized that anterior tibial osteophyte (ATO) is also associated with anterior meniscus extrusion (AME). Thus, we aimed to examine their prevalence and relationship. Methods: Elderly subjects (638 females and 507 males; average 72.9 years old) in the Bunkyo Health Study cohort were enrolled. MRI-detected OA changes were evaluated according to the Whole Organ Magnetic Resonance Imaging Score. ATO was evaluated using the method which can assess both cartilage and bone parts of osteophyte by pseudo-coloring images of proton density-weighted fat-suppressed MRI. Results: Most subjects showed the Kellgren-Lawrence grade 1/2 of the medial knee OA (88.1%), AME (94.3%, 3.7 â€‹± â€‹2.2 â€‹mm), and ATO (99.6%, 4.2 â€‹± â€‹1.5 â€‹mm). Among the OA changes, AME was most closely associated with full-length width of ATO (multivariable ߠ​= â€‹0.877, p â€‹< â€‹0.001). The area under the receiver operating characteristic curve for determining the presence of AME as evaluated by ATO width was 0.75 (95% confidence interval 0.60-0.84, p â€‹< â€‹0.001). The odds ratio for the presence of AME as evaluated by ATO width at 2.9 â€‹mm was 7.16 (4.23-12.15, p â€‹< â€‹0.001, age, gender, BMI, and K-L adjusted). Conclusions: AME and ATO were inevitably observed in the elderly subjects and AME was closely associated with full-length width of ATO. Our study provides the first evidence on the close relationship between AME and ATO in knee OA.

Medial meniscus extrusion is directly correlated with medial tibial osteophyte in patients received reconstruction surgery for anterior cruciate ligament injury: A longitudinal study.

Objective: Anterior cruciate ligament (ACL) injury is one of the causes for post-traumatic knee osteoarthritis (OA), and ACL reconstruction surgery is reportedly unable to prevent OA development. In early-stage knee OA, medial meniscus extrusion (MME) is closely correlated with tibial medial osteophyte width, which consists of bone and cartilage -parts. However, the relationship between MME and osteophyte in ACL-injured patients remains elusive. We examined MME and osteophyte and their relationship in ACL-injured patients before and after surgery. Design: Thirty ACL-injured patients who underwent surgery (30.7 years old, on average) were enrolled. Correlations between magnetic resonance imaging (MRI)-detected OA changes and MME before and after surgery (7.6 months interval) were analyzed. Results: MME (>3 â€‹mm) was present in 16.7% and 26.7% of the patients before and after surgery, respectively, and MME was significantly increased after surgery (2.4 â€‹± â€‹1.3 â€‹mm) than before surgery (1.9 â€‹± â€‹1.2 â€‹mm) (p â€‹< â€‹0.0001). Full-length tibial osteophyte width measured by T2 mapping MRI was significantly increased after surgery (1.9 â€‹± â€‹0.7 â€‹mm) than before surgery (1.4 â€‹± â€‹0.6 â€‹mm) (p â€‹< â€‹0.0001). Among OA structural changes, only medial tibial osteophyte width directly correlated with MME before surgery (ߠ​= â€‹0.962) (p â€‹< â€‹0.001) and after surgery (ߠ​= â€‹0.928) (p â€‹= â€‹0.001). All the patients with MME had medial tibial osteophyte before and after surgery. A direct correlation was observed between changes of MME and those of medial tibial osteophyte width before and after surgery (r â€‹= â€‹0.63) (p â€‹< â€‹0.0001). Conclusion: MME and medial tibial osteophyte were simultaneously increased after surgery. In addition to close correlation between MME and medial tibial osteophyte width, changes of MME and medial tibial osteophyte width before and after surgery were directly correlated.

Validation and defining the minimal clinically important difference of the Japanese version of the IKDC Subjective Knee Form.

BACKGROUND: This study aimed to validate and determine the minimal clinically important difference (MCID) in the Japanese version of the International Knee Documentation Committee Subjective Knee Form (Japanese IKDC-SKF) for patients with anterior cruciate ligament (ACL) injuries. METHODS: This prospective study was performed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guideline to assess the measurement properties of reliability, responsiveness, validity, and interpretability of the Japanese IKDC-SKF. RESULTS: A total of 152 patients were enrolled in the study. The Japanese IKDC-SKF had excellent internal consistency [Cronbach's alpha (95% confidence interval, CI) was 0.90 (0.88-0.92), and the test-retest reliability [intraclass correlation coefficient, ICC2,1 (95% CI)] was 0.97 (0.94-0.98). The content validity (r), which was interpretable between the Japanese IKDC-SKF and the Japanese Anterior Cruciate Ligament questionnaire 25 was -0.87 (P < 0.001). The construct validity for the IKDC-SKF was 86% (six of seven hypotheses were consistent with the results), also indicating high validity. Responsiveness of the Japanese IKDC-SKF was confirmed, with an acceptable area under the curve of 0.81 and a large effect size (Cohen's d of 0.8). There were no floor or ceiling effects. The MCID for the Japanese IKDC-SKF for ACL injury was 10.7. CONCLUSIONS: Our results indicate that the Japanese version of the IKDC-SKF is a reliable, valid, and responsive measurement instrument with which to evaluate the physical function of patients with ACL injuries.

Medial meniscus extrusion is a determinant factor for the gait speed among MRI-detected structural alterations of knee osteoarthritis.

Objective: Knee osteoarthritis (OA) is one of the most common causes for reduction in gait speed. Research into the mechanism of underlying knee OA pain and other symptoms such as the reduction in the gait speed is essential to development of disease-modifying treatments for knee OA. We examined the magnetic resonance imaging (MRI)-detected structural alterations in knee joints those were associated with gait speed in knee OA patients. Design: In this cross-sectional study, structural alterations in knee joints of 74 knee OA patients (51 females; mean 72.2 years old) were evaluated by MRI, and subjects' gait speed was measured. Results: The mean self-selected gait speed of the subjects was 0.73 â€‹± â€‹0.21 â€‹m/s. A simple linear regression analysis revealed that MME was only correlated with the gait speed of the subjects with knee OA, while cartilage lesion, bone marrow lesion, subchondral bone cyst, subchondral cyst, osteophytes and meniscal pathology were not. A multiple regression analysis revealed that only MME was associated with gait speed (R2 â€‹= â€‹0.484, p â€‹< â€‹0.001). The area under the receiver operating characteristic curve for determining <0.8 â€‹m/s of gait speed as evaluated by MME were 0.72 (95% confidence interval: 0.60-0.84). The relative risks at a cut-off <0.8 â€‹m/s for gait speed as evaluated by MME at 6.2 â€‹mm were 2.19 (1.28-3.46, p â€‹= â€‹0.01). Conclusions: MME was associated with and the determinant for gait speed among MRI-detected structural alterations in patients with knee OA, suggesting the importance for elucidating the etiology of MME for developing a disease-modifying treatment for knee OA.

Reproducibility, responsiveness and validation of the Tampa Scale for Kinesiophobia in patients with ACL injuries.

BACKGROUND AND PURPOSE: Psychological factors including fear of pain, re-injury during movement (kinesiophbia) affect return-to-sport rates after anterior cruciate ligament (ACL) reconstructive surgery. Clinicians often encounter in the daily practice that athletes explain lack of self-confidence or psychological readiness during the sports activity. The Tampa Scale for Kinesiophobia (TSK) has been used to evaluate psychological outcomes in patients with ACL injuries in many countries and translated into Japanese version in 2013. However, no researchers validated its reliability, validity, and responsiveness of TSK for patients with ACL injury up to now. The purpose of this study was to evaluate the measurement properties of the Japanese version of the TSK (TSK-J) in patients with ACL injuries. STUDY DESIGN: Cohort study (Diagnostic); Level of evidence, 2. METHODS: This prospective study was performed in the department of orthopaedic surgery at the university hospital of Juntendo from Sep 2016 and Apr 2017. Patients who diagnosed with ACL injury with or without reconstruction surgery completed several patient-reported outcome measures (PROMs) were included in this study. The COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines were used to evaluate reliability, validity, responsiveness, and interpretability of the TSK-J. RESULTS: 222 patients were included in this study. The TSK-J for ACL injured patients showed good internal consistency (Cronbach's alpha = 0.79) and excellent test-retest reliability (intra-class correlation coefficient, ICC2,1 = 0.90, 95% CI = 0.81 to 0.95). In addtion, the TSK-J was significantly but moderately correlated with the IKDC-SKF (r = - 0.49, P <0.001), VAS-Sports (r = - 0.48, P <0.001), and JACL-25 (r = 0.48, P <0.001). The effect size (ES) was small with the Cohen's d = - 0.2. The minimal important difference (MID) was - 1.3 points. No significant TSK-J score change was observed over 1-year after ACL reconstruction (r = - 0.12, P <0.001). There were no floor or ceiling effects. CONCLUSIONS: Our study demonstrated that the Japanese version of TSK has good reliability. However, its low validity and responsiveness indicate that it may not the best way to assess psychological factors for patients with ACL injury.

The increase in bone mineral density by bisphosphonate with active vitamin D analog is associated with the serum calcium level within the reference interval in postmenopausal osteoporosis.

OBJECTIVES: To examine the factors associated with increase in lumbar spine bone mineral density (LS-BMD) by bisphosphonates (BPs) with active vitamin D analog (aVD). METHODS: Two independent postmenopausal osteoporotic patients treated by BPs with aVD for 24 months (Study 1: n = 93, Study 2: n = 99) were retrospectively analyzed. RESULTS: In Study 1, LS-BMD of the patients significantly increased for 24 m (5.4%, p < .001). A multiple regression analysis among baseline characteristics revealed that serum calcium (sCa: 8.5-10.5 mg/dL) was associated with an increased LS-BMD by treatment (r2: 0.088, p = .02). While average sCa of the patients was 9.2 mg/dL before treatment, it increased time-dependently to 9.6 mg/dL for 24 m by treatment. As each patient had their LS-BMD five times during the study, there were four instances of %LS-BMD in each patient, resulting in 372 instances of %LS-BMD in Study 1. The smallest Akaike's information criterion value for the most appropriate cut-off levels of sCa for %LS-BMD by treatment every 6 m was 9.3 mg/dL. The %LS-BMD by treatment for 6 m during 24 m period in patients with sCa ≥9.3 mg/dL (1.5%) was significantly higher than that in patients with sCa <9.3 mg/dL (0.8%, p = .038). The results of Study 2 were similar to those of Study 1, confirming the phenomena observed. CONCLUSION: sCa was associated with an increased LS-BMD by BPs with aVD.

Association of medial meniscal extrusion with medial tibial osteophyte distance detected by T2 mapping MRI in patients with early-stage knee osteoarthritis.

BACKGROUND: Medial meniscal extrusion (MME) is associated with progression of medial knee osteoarthritis (OA), but no or little information is available for relationships between MME and osteophytes, which are found in cartilage and bone parts. Because of the limitation in detectability of the cartilage part of osteophytes by radiography or conventional magnetic resonance imaging (MRI), the rate of development and size of osteophytes appear to have been underestimated. Because T2 mapping MRI may enable us to evaluate the cartilage part of osteophytes, we aimed to examine the association between MME and OA-related changes, including osteophytes, by using conventional and T2 mapping MRI. METHODS: Patients with early-stage knee OA (n = 50) were examined. MRI-detected OA-related changes, in addition to MME, were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. T2 values of the medial meniscus and osteophytes were measured on T2 mapping images. Osteophytes surgically removed from patients with end-stage knee OA were histologically analyzed and compared with findings derived by radiography and MRI. RESULTS: Medial side osteophytes were detected by T2 mapping MRI in 98% of patients with early-stage knee OA, although the detection rate was 48% by conventional MRI and 40% by radiography. Among the OA-related changes, medial tibial osteophyte distance was most closely associated with MME, as determined by multiple logistic regression analysis, in the patients with early-stage knee OA (ß = 0.711, p < 0.001). T2 values of the medial meniscus were directly correlated with MME in patients with early-stage knee OA, who showed ≥ 3 mm of MME (r = 0.58, p = 0.003). The accuracy of osteophyte evaluation by T2 mapping MRI was confirmed by histological analysis of the osteophytes removed from patients with end-stage knee OA. CONCLUSIONS: Our study demonstrates that medial tibial osteophyte evaluated by T2 mapping MRI is frequently observed in the patients with early-stage knee OA, showing close association with MME, and that MME is positively correlated with the meniscal degeneration.

The MRI-detected osteophyte score is a predictor for undergoing joint replacement in patients with end-stage knee osteoarthritis.

OBJECTIVES: The aim of this prospective cohort study was to examine whether MRI-detected osteoarthritis (OA)-structural changes at baseline could predict knee OA patients who would undergo total knee arthroplasty (TKA). METHODS: In total, 128 end-stage medial-type knee OA patients were enrolled and followed up for 6 months. MRI using the whole-organ MRI scoring (WORMS) method, radiographic findings, visual analog scale (VAS) for pain and a patient-oriented outcome measure, and the Japanese Knee Osteoarthritis Measure (JKOM) were recorded at baseline. The area under the curve (AUC) was estimated to determine the discriminative value of the prediction models. RESULTS: While 74 patients (57.8%) did not undergo TKA, the remaining 54 patients (42.2%) underwent TKA during this period. The AUCs of the receiver operating characteristic (ROC) curve for the activities of daily living (ADL) score evaluated by the JKOM ADL score [0.70 (95% CI: 0.60-0.79)] and osteophyte score [0.72 (0.64-0.81)] were 0.70 or greater. The JKOM ADL score (17/40) and the osteophyte score (30/98) showed relative risks (RR) of 2.61 (1.32-5.15) and 3.01 (1.39-6.52) for undergoing TKA, respectively. CONCLUSION: The osteophyte score detected by MRI, in addition to ADL score, was found to be an important factor in determining whether the patient should undergo TKA.

Group X secretory phospholipase A2 can induce arachidonic acid release and eicosanoid production without activation of cytosolic phospholipase A2 alpha.

Group X secretory phospholipase A2 (sPLA2-X) and cytosolic phospholipase A2 alpha (cPLA2alpha) are involved in the release of arachidonic acid (AA) from membrane phospholipids linked to the eicosanoid production in various pathological states. Recent studies have indicated the presence of various types of cross-talk between sPLA2s and cPLA2alpha resulting in effective AA release. Here we examined the dependence of sPLA2-X-induced potent AA release on the cPLA2alpha activation by using specific cPLA2alpha or sPLA2 inhibitors as well as cPLA2alpha-deficient mice. We found that Pyrrophenone, a cPLA2alpha-specific inhibitor, did not suppress the sPLA2-X-induced potent AA release and prostaglandin E2 formation in mouse spleen cells. Furthermore, the amount of AA released by sPLA2-X from spleen cells was not significantly altered by cPLA2alpha deficiency. These results suggest that sPLA2-X induces potent AA release without activation of cPLA2a, which might be relevant to eicosanoid production in some pathological states where cPLA2a is not activated.

Role of group IIA phospholipase A2 in rat colitis induced by dextran sulfate sodium.

Although group IIA phospholipase A(2) has been suggested to be implicated in inflammatory bowel disease, its pathophysiological role in colitis remains unclear. We investigated whether group IIA phospholipase A(2) had pro-inflammatory roles in dextran sulfate sodium-induced colitis in the rat. Secretory phospholipase A(2) activity was markedly increased in the distal colon with two peaks. Strong immunostaining for group IIA phospholipase A(2) was found in subepithelial tissue and lamina propria at early stage and in deeper tissues of the erosion area at later stage. Treatment with a specific group IIA phospholipase A(2) inhibitor, S-3013/LY333013 (methyl[[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)]-1H-indol-4yl]oxy) acetate), reduced erosion area, shortening of colon and colonic inflammation, and strongly inhibited the increase in secretory phospholipase A(2) activity and moderately reduced myeloperoxidase activity in the colon in vivo, while eicosanoid levels were not affected. Marked group IIA phospholipase A(2) expression in the erosion area and the improvement of colitis by the group IIA phospholipase A(2) inhibitor strongly suggest that this enzyme plays pro-inflammatory roles in this colitis model.

Phospholipase A2 receptor: a regulator of biological functions of secretory phospholipase A2.

The phospholipase A2 receptor (PLA2R) is a type I transmembrane glycoprotein related to the C-type animal lectin family that includes the mannose receptor. PLA2R regulates a variety of biological responses elicited by specific types of secretory PLA2s (sPLA2s). Group IB sPLA2 (sPLA2-IB) acts as an endogenous PLA2R ligand to induce cell proliferation, cell migration, and lipid mediator production. Analysis of PLA2R-deficient mice has suggested a potential role of the sPLA2-IB/PLA2R pathway in the production of pro-inflammatory cytokines in endotoxic shock. PLA2R is also involved in the clearance of sPLA2s, including group X sPLA2 (sPLA2-X) and a particular type of snake venom sPLA2, and clearance suppresses their potent enzymatic activities. In the circulation, the soluble form of PLA2R is constitutively present as anendogenous inhibitor of sPLA2s. This review will focus on recent findings on the roles of PLA2R in regulating sPLA2 functions and summarize what is known about the otherbinding proteins for mammalian and snake venom sPLA2s.

Presence of the M-type sPLA(2) receptor on neutrophils and its role in elastase release and adhesion.

Secretory phospholipase A(2) (sPLA(2)) produces lipids that stimulate polymorphonuclear neutrophils (PMNs). With the discovery of sPLA(2) receptors (sPLA(2)-R), we hypothesize that sPLA(2) stimulates PMNs through a receptor. Scatchard analysis was used to determine the presence of a sPLA(2) ligand. Lysates were probed with an antibody to the M-type sPLA(2)-R, and the immunoreactivity was localized. PMNs were treated with active and inactive (+EGTA) sPLA(2) (1-100 units of enzyme activity/ml, types IA, IB, and IIA), and elastase release and PMN adhesion were measured. PMNs incubated with inactive, FITC-linked sPLA(2)-IB, but not sPLA(2)-IA, demonstrated the presence of a sPLA(2)-R with saturation at 2.77 fM and a K(d) of 167 pM. sPLA(2)-R immunoreactivity was present at 185 kDa and localized to the membrane. Inactive sPLA(2)-IB activated p38 MAPK, and p38 MAPK inhibition attenuated elastase release. Active sPLA(2)-IA caused elastase release, but inactive type IA did not. sPLA(2)-IB stimulated elastase release independent of activity; inactive sPLA(2)-IIA partially stimulated PMNs. sPLA(2)-IB and sPLA(2)-IIA caused PMN adhesion. We conclude that PMNs contain a membrane M-type sPLA(2)-R that activates p38 MAPK.

Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation.

The deposition of cholesterol ester within foam cells of the artery wall is fundamental to the pathogenesis of atherosclerosis. Modifications of low density lipoprotein (LDL), such as oxidation, are prerequisite events for the formation of foam cells. We demonstrate here that group X secretory phospholipase A2 (sPLA2-X) may be involved in this process. sPLA2-X was found to induce potent hydrolysis of phosphatidylcholine in LDL leading to the production of large amounts of unsaturated fatty acids and lysophosphatidylcholine (lyso-PC), which contrasted with little, if any, lipolytic modification of LDL by the classic types of group IB and IIA secretory PLA2s. Treatment with sPLA2-X caused an increase in the negative charge of LDL with little modification of apolipoprotein B (apoB) in contrast to the excessive aggregation and fragmentation of apoB in oxidized LDL. The sPLA2-X-modified LDL was efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of non-membrane-bound lipid droplets in the cytoplasm, whereas the extensive accumulation of multilayered structures was found in the cytoplasm in oxidized LDL-treated macrophages. Immunohistochemical analysis revealed marked expression of sPLA2-X in foam cell lesions in the arterial intima of high fat-fed apolipoprotein E-deficient mice. These findings suggest that modification of LDL by sPLA2-X in the arterial vessels is one of the mechanisms responsible for the generation of atherogenic lipoprotein particles as well as the production of various lipid mediators, including unsaturated fatty acids and lyso-PC.

Identification of a soluble form phospholipase A2 receptor as a circulating endogenous inhibitor for secretory phospholipase A2.

Venomous snakes have various types of phospholipase A(2) inhibitory proteins (PLIs) in their circulatory system to protect them from attack by their own phospholipase A(2)s (PLA(2)s). Here we show the first evidence for the existence of circulating PLI against secretory PLA(2)s (sPLA(2)s) in mammals. In mouse serum, we detected specific binding activities of group IB and X sPLA(2)s, which was in contrast with the absence of binding activities in serum prepared from mice deficient in PLA(2) receptor (PLA(2)R), a type I transmembrane glycoprotein related to the C-type animal lectin family. Western blot analysis after partial purification with group IB sPLA(2) affinity column confirmed the identity of serum sPLA(2)-binding protein as a soluble form of PLA(2)R (sPLA(2)R) that retained all of the extracellular domains of the membrane-bound receptor. Both purified sPLA(2)R and the recombinant soluble receptor having all of the extracellular portions blocked the biological functions of group X sPLA(2), including its potent enzymatic activity and its binding to the membrane-bound receptor. Protease inhibitor tests with PLA(2)R-overexpressing Chinese hamster ovary cells suggested that sPLA(2)R is produced by cleavage of the membrane-bound receptor by metalloproteinases. Thus, sPLA(2)R is the first example of circulating PLI that acts as an endogenous inhibitor for enzymatic activities and receptor-mediated functions of sPLA(2)s in mice.