IL-6 Reduces Spheroid Sizes of Osteophytic Cells Derived from Osteoarthritis Knee Joint via Induction of Apoptosis.

Osteophytes in osteoarthritis (OA) joints contribute to restriction of joint movement, joint pain, and OA progression, but little is known about osteophyte regulators. Examination of gene expression related to cartilage extracellular matrix, endochondral ossification, and growth factor signaling in articular cartilage and osteophytes obtained from OA knee joints showed that several genes such as COL1A1, VCAN, BGLAP, BMP8B, RUNX2, and SOST were overexpressed in osteophytes compared with articular cartilage. Ratios of mesenchymal stem/progenitor cells, which were characterized by co-expression of CD105 and CD166, were significantly higher in osteophytic cells than articular cells. A three-dimensional culture method for cartilage and osteophyte cells was developed by modification of cultures of self-assembled spheroid cell organoids (spheroids). These spheroids cultured in the media for mesenchymal stem cells containing transforming growth factor-ß3 showed characteristic morphologies and gene expression profiles of articular cartilage and osteophytes, respectively. The effects of IL-1ß, tumor necrosis factor-α, and IL-6 on the spheroids of articular and osteophytic cells were studied. To the best of our knowledge, they provide the first evidence that IL-6 suppresses the spheroid size of osteophytic cells by inducing apoptosis and reducing extracellular matrix molecules. These data show that IL-6 is the suppressor of osteophyte growth and suggest that IL-6 expression and/or activity are implicated in the regulation of osteophyte formation in pathologic joints.

Higher fibular head is a risk for lateral hinge fracture in medial open wedge high tibial osteotomy.

PURPOSE: To examine the association between the hinge position, fibular head position, and type III lateral hinge fracture (LHF) in patients with knee osteoarthritis (OA) who underwent medial open wedge high tibial osteotomy (MOWHTO). METHODS: This retrospective study examined patients who underwent MOWHTO. Radiographically, the Kellgren-Lawrence (K/L) classification, distance between the articular surface and the tip of the fibular head (fibular head position), hinge point (hinge position), type of LHF, and safe zone (within the proximal tibiofibular joint) outlier were evaluated. To determine the cut-off value of the hinge position and fibular head position associated with type III LHF, a receiver operating characteristic (ROC) curve analysis was performed. The odds ratio (OR) was calculated from the obtained cut-off values using logistic regression, which was adjusted by age, gender, body mass index, and opening distance. RESULTS: Among 132 knees in 120 patients, the radiographic severity of knee OA was 19 (14%), 73 (55%), and 40 (30%) of K/L grades 2, 3, and 4, respectively. LHF was observed in 40 knees (30%), including types I, II, and III fractures in 21 (16%), 5 (4%), and 14 (11%) knees, respectively. Hinge and fibular head positions were 16 and 10 mm, respectively, with significant correlation. Safe zone outlier was observed in 38 knees (29%). The hinge and fibular head positions with type III LHF were significantly higher (more cranial) than those with no fracture or other LHF subtypes. The ROC curve revealed that the cut-off value for the hinge and fibular head positions was 13.3 and 8.6 mm, respectively. The OR of the hinge and fibular head positions was 22.42 and 13.86, respectively. CONCLUSIONS: A higher hinge position was a risk factor for type III LHF and was associated with a higher fibular head in patients with knee OA who underwent MOWHTO. The hinge position should be placed at a certain distance from the articular surface to avoid type III LHF, especially in participants with higher fibular head position, even if the hinge position is located in the safe zone. LEVEL OF EVIDENCE: Retrospective cohort study, Level III.

Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family includes nine members with aggrecan-degrading activity, i.e., ADAMTS1, 4, 5, 8, 9, 15, 16, 18, and 20. However, their systematic expression profile in knee osteoarthritis (OA) synovium and effects of cytokines and growth factors on the expression in OA synovial fibroblasts remain elusive. In this study, expression of all nine aggrecanolytic ADAMTS species was assessed by quantitative real-time PCR in OA and control normal synovial tissues. OA synovial fibroblasts were treated with interleukin-1α (IL-1α), IL-1ß, tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), vascular endothelial growth factor165, and heparin-binding epidermal growth factor, and analyzed for the expression of the ADAMTS species. The signaling pathways and inhibition of ADAMTS4 expression by high-molecular-weight hyaluronan, adalimumab, tocilizumab, and signaling molecule inhibitors were studied. ADAMTS1, 4, 5, 9, and 16 were expressed in OA synovium, but only ADAMTS4 expression was significantly higher in OA as compared to normal synovium. IL-1α, TNF-α, and TGF-ß markedly increased ADAMTS4 expression, while their effects were minimal for the other ADAMTS species. ADAMTS4 was synergistically upregulated by treatment with IL-1α and TNF-α, IL-1α and TGF-ß, or IL-1α, TNF-α and TGF-ß. The signaling molecules' inhibitors demonstrated that IL-1α-induced ADAMTS4 expression is predominantly through TGF-ß-associated kinase 1 (TAK1), and the TNF-α-stimulated expression is via TAK1 and nuclear factor-κB (NF-κB). The TGF-ß-promoted expression was through the activin receptor-like kinase 5 (ALK5)/Smad2/3, TAK1, and non-TAK1 pathways. Adalimumab blocked TNF-α-stimulated expression. ADAMTS4 expression co-stimulated with IL-1α, TNF-α and TGF-ß was abolished by treatment with adalimumab, TAK1 inhibitor, and ALK5/Smad2/3 inhibitor. These data demonstrate marked and synergistic upregulation of ADAMTS4 by IL-1α, TNF-α and TGF-ß in OA synovial fibroblasts, and suggest that concurrent therapy with an anti-TNF-α drug and inhibitor(s) may be useful for prevention against aggrecan degradation in OA.

Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid-/-) mice compared with wild-type mice. Hybid was highly produced by synovial cells and articular chondrocytes in the osteoarthritis joints of wild-type mice. IL-1ß, IL-6, and tumor necrosis factor-α were up-regulated in the osteoarthritis joint tissues of both wild-type and Hybid-/- mice. Vascular density at the synovial and periosteal junction was significantly reduced in Hybid-/- mice compared with wild-type mice. High-molecular-weight HA accumulated in osteoarthritis joint tissues of Hybid-/- mice. Injections of high-molecular-weight HA to knee joints attenuated the cartilage destruction and osteophyte formation in wild-type mouse osteoarthritis group. Inhibition of cartilage destruction and osteophyte formation in Hybid-/- mice was also observed in destabilization of the medial meniscus model. These data are the first to demonstrate that cartilage destruction and osteophyte formation are suppressed in Hybid-/- mice and suggest that Hybid-mediated HA depolymerization is implicated for the progression of mechanically-induced knee osteoarthritis.

Zoledronic Acid Deteriorates Soft and Hard Tissue Healing of Murine Tooth Extraction Sockets in a Dose-Dependent Manner.

The pathophysiology, histopathology, and immunopathology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) Stage 0 remain unclear. The aim of this study was to investigate the effects of high-dose bisphosphonates on tooth extraction socket healing by creating a murine model of BRONJ Stage 0-like lesions using 8-week-old female C57BL/6J mice. Zoledronic acid (Zol) was administered subcutaneously twice a week for 7 weeks at doses of 0.1 mg/kg/week (moderate dose; Zol-M), 0.5 mg/kg/week (high dose; Zol-H1), and 1.0 mg/kg/week (higher dose; Zol-H2). Saline was used as a control (VC). Both maxillary first molars were extracted 3 weeks after drug treatment. Maxillae, long bones, and sera were collected 4 weeks post-extraction (n = 7 mice/group). Microcomputed tomography, histological, immunohistochemical, and ELISA analyses were performed. A ceiling effect for Zol was noted at the Zol-H1 dose. Osseous healing of extraction sites was significantly impaired with increased necrotic bone and the number of empty lacunae in a Zol dose-dependent manner. Zol significantly decreased epithelial thickness, due to a decrease in thickness of the stratum spinosum, in both Zol-H1 and Zol-H2. Both Zol-H1 and Zol-H2 significantly suppressed the distribution of F4/80+ macrophages in the connective tissue of tooth extraction sockets, although gross healing appeared to be normal. Intriguingly, both Zol-H1 and Zol-H2 significantly increased the numbers of TRAP+ mononuclear cells and detached osteoclasts in the connective tissue and bone marrow of extraction sites compared to VC and Zol-M, correlated with serum TRAcP5b levels. The created murine model of BRONJ Stage 0-like lesions becoming more severe in a dose-dependent manner may help to understand the pathophysiology and histopathology of BRONJ Stage 0 in humans.

Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis.

Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), plays a role in HA degradation. CEMIP2, also known as transmembrane protein 2 (TMEM2), possessing a sequence similarity with HYBID, is reported as a hyaluronidase in mice. However, the expression of these molecules in osteoarthritic synovium and their involvement in HA degradation in synovial fluid (SF) from patients with knee osteoarthritis remain elusive. This study examined their expression in synovial tissue and the relationship with molecular weight of HA in SF in knee osteoarthritis patients. Quantification of mRNA demonstrated that HYBID expression is significantly (5.5-fold) higher in osteoarthritic synovium than in normal control synovium, whereas TMEM2 expression level is similar between the two groups. By immunohistochemistry, HYBID was localized mainly to CD68-negative and fibroblast-specific protein 1-positive synovial lining cells and sublining fibroblasts in osteoarthritic synovium. The mRNA expression levels of HYBID, but not TMEM2, in osteoarthritic synovium positively correlated with distribution of lower-molecular-weight HA with below 1000 kDa in SF. HA-degrading activity in osteoarthritic synovial fibroblasts was abrogated by siRNA-mediated knockdown of HYBID. Among the 12 factors examined, IL-6 significantly up-regulated the HYBID expression and HA-degrading activity in osteoarthritic synovial fibroblasts. These data suggest that HYBID overexpressed by IL-6-stimulated synovial fibroblasts is implicated in HA degradation in osteoarthritic synovium.

Remnant preservation provides good clinical outcomes after anterior cruciate ligament reconstruction.

PURPOSE: To evaluate the association of remnant preservation (RP) and non-RP (NRP) with patient-reported outcome measures and subsequent graft rupture at a minimum 2-year follow-up after anterior cruciate ligament (ACL) reconstruction. METHODS: Patients in this retrospective study underwent primary isolated ACL reconstruction by the RP or NRP technique with a four- to five-strand hamstring tendon graft. Multivariate linear or logistic regression and Cox regression analyses were performed to compare the physical and psychological outcomes by the International Knee Documentation Committee subjective knee form (IKDC-SKF) and the Japanese Anterior Cruciate Ligament questionnaire 25 (JACL-25), respectively; satisfaction rate; and prognosticators of graft rupture. RESULTS: In total, 120 patients (mean age, 30.6 ± 12.7 years; 54 RP, 66 NRP) with a mean follow-up of 3.2 ± 1.6 years were enrolled in this study. At the latest postoperative follow-up, the RP group showed a mean IKDC-SKF score of 92.3 ± 8.5 and mean JACL-25 score of 13.2 ± 11.2, while these scores in the NRP group were 86.4 ± 12.2 and 24.4 ± 19.5, respectively (P = 0.016 and 0.007, respectively). No significant differences were found in the return-to-sports rate (RP vs. NRP, 79.5% vs. 67.5%) or satisfaction rate (RP vs. NRP, 89.2% vs. 74.4%) (n.s.); however, a significant difference was found in the rate of return to the preinjury sports level (RP vs. NRP, 64.1% vs. 37.5%; P = 0.014). The graft rupture rate was significantly higher in the NRP than RP group (9/66 vs. 1/54; hazard ratio 9.29; 95% confidence interval 1.04-82.81). Younger age (≤ 18 years) was the other important risk factor for graft rupture (hazard ratio 8.67; 95% confidence interval 2.02-37.13). CONCLUSION: Patients who underwent ACL reconstruction with the RP technique obtained somewhat better physical and psychological results than those who underwent ACL reconstruction with the NRP technique. With respect to clinical relevance, patients treated with the RP technique may obtain better outcomes in terms of graft rupture and return to the preinjury sports level than those treated with the NRP technique, but with no differences in overall return to sports or satisfaction. LEVEL OF EVIDENCE: IV.

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.

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.

The Relationship between Mismatch Negativity and the COMTVal108/158Met Genotype in Schizophrenia.

Mismatch negativity (MMN) is a component of auditory event-related potentials that reflects automatic change detection in the brain, showing qualities of endophenotypes in schizophrenia. MMN deficiency is one of the robust findings in patients, and it reflects both cognitive and functional decline. Catechol-o-methyltransferase (COMT) is a key enzyme involved in regulating dopamine transmission within the prefrontal cortex. A preliminary study suggested that the COMTVal108/158Met genotype (rs4680) is related to cognitive function in schizophrenia. Both the COMTVal108/158Met genotype and MMN are related to cognitive function, but no studies have reported on the relationship between MMN and the COMTVal108/158Met genotype in schizophrenia. This study therefore examined the relationship between COMTVal108/158Met genotype and MMN. The duration of MMN was measured, and the COMTVal108/158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 49 Japanese schizophrenia patients (Val/Val, n = 21; Met carriers, n = 28). Amplitude and latency of MMN were compared between Val/Val and Met carriers.

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.

Low- and high-dose aripiprazole augmentation and plasma levels of homovanillic acid in major depressive disorder: A randomized, open-label study.

OBJECTIVE: This randomized controlled study evaluated the efficacy of low-dose (LD) and high-dose (HD) aripiprazole augmentation in major depressive disorder. Additionally, we examined the relationship between clinical response and changes in plasma homovanillic acid (pHVA) levels during aripiprazole augmentation. METHODS: Thirty-one patients with inadequate response to antidepressants were randomized to receive adjunctive treatment with LD (3 mg/day, n = 17) or HD (up to 12 mg/day, n = 14) aripiprazole for 6 weeks. We evaluated the Montgomery-Åsberg Depression Rating Scale (MADRS) and measured pHVA at baseline, Week 2, and end point. RESULTS: Both LD and HD aripiprazole significantly decreased MADRS score after 6 weeks, and the response rate was higher in HD aripiprazole group at end point. HD aripiprazole significantly decreased MADRS score at Week 2 compared with LD aripiprazole (p = .015). There was a significant difference in changes in pHVA between responders and nonresponders, showing pHVA decreased significantly in responders at Week 2 (p = .044). CONCLUSIONS: Increasing aripiprazole from the early period appeared useful for immediate response, although caution is needed when increasing the dose >6 mg/day. pHVA may be a possible indicator of the response to aripiprazole augmentation. Caution is needed in interpreting these findings because of the small sample size.

The medial proximal tibial angle accurately corrects the limb alignment in open-wedge high tibial osteotomy.

PURPOSE: The purpose of this study was to detect the pre- and intra-operative influential factors for lower limb alignment correction error in open-wedge high tibial osteotomy (OWHTO). METHODS: This study involved 69 patients (71 knees) undergoing OWHTO for primary medial osteoarthritis. The weight-bearing line (WBL) ratio, medial proximal tibial angle (MPTA), and joint line convergence angle (JLCA) were measured on radiographs preoperatively and at 1 month after surgery, and the differences between the pre- and postoperative values were calculated. The correction angle during surgery was also investigated. The radiological correction angle was defined as the difference between the pre- and postoperative MPTA. The correction error was defined as the difference between the correction angle during surgery and the radiological correction angle. The ideal correction angle was defined as when the postoperative WBL passed through Fujisawa's point (WBL = 62.5%), and the alignment error was defined as the difference between the postoperative WBL ratio and 62.5. The correlations among the alignment error, the correction error, correction angle during surgery, pre- and postoperative WBL ratio, MPTA, and JLCA and the differences between the pre and postoperative WBL ratio, MPTA, and JLCA were investigated. In addition, the factor most influential on the alignment error was determined. RESULTS: The preoperative MPTA was the only predictor of the alignment error after OWHTO. The alignment error was positively correlated with the correction error and correction angle during surgery, and negatively correlated with pre- and postoperative WBL ratio, MPTA, and differences between the pre- and postoperative WBL ratio and JLCA. CONCLUSION: The preoperative MPTA was the only pre- and intra-operative predictor of the alignment error after OWHTO. The larger the correction angle, the greater the alignment error. The MPTA was recommended as an indicator for improving the correction accuracy. Accurate correction based on the MPTA provides good lower limb alignment and better clinical results. LEVEL OF EVIDENCE: III Case-control study/Retrospective comparative study.

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 between leg bowing and serum alkaline phosphatase level regardless of the presence of a radiographic growth plate abnormality in pediatric patients with genu varum.

When children around 2 years of age show leg bowing and diseases are ruled out based on radiographic findings without conducting blood tests, they are classified as "physiologic" genu varum. Since whether or not physiologic genu varum is associated with bone metabolism is unclear, this study was conducted to clarify the association between genu varum and bone metabolism in children. Thirty-five pediatric patients with genu varm who visited our out-patient clinic were enrolled. While two of the 35 children had nutritional rickets, showing abnormalities on both blood test (ALP, ≥1000 IU/L; iPTH, >65 pg/mL and 25(OH)D, ≤20 ng/mL) and radiographs (such as cupping, fraying or splaying), five of 35 children showed abnormalities on blood tests but not radiographs. While metaphyseal-diaphyseal angle (MDA) correlated with serum 25-hydroxy vitamin D (r = -0.35, p = 0.04) and magnesium (r = -0.36, p = 0.04), MDA and femorotibial angle (FTA) correlated with alkaline phosphatase (r = 0.43, p = 0.01 and r = 0.51, p = 0.006, respectively). A ridge regression analysis adjusted for age and body mass index indicated that ALP was associated with MDA and FTA. A logistic regression analysis adjusted for age and BMI indicated that higher ALP influenced an MDA >11°, which indicates the risk for the progression of genu varum (odds ratio 1.002, 95% confidence interval 1.0003-1.003, p = 0.021). The higher ALP (+100 IU), the higher risk of an MDA >11° (odds ratio 1.22). In conclusion, genu varum is associated with the alkaline phosphatase level regardless of the presence of radiographic abnormalities in the growth plate in children.

Comparison of mesenchymal stem cells obtained by suspended culture of synovium from patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Mobilization of mesenchymal stem cells (MSCs) from the synovium was revealed using a "suspended synovium culture model" of osteoarthritis (OA). The pathology of rheumatoid arthritis (RA) differs from that of OA. We investigated whether mobilization of MSCs from the synovium also occurred in RA, and we compared the properties of synovial MSCs collected from suspended synovium culture models of RA and OA. METHODS: Human synovium was harvested during total knee arthroplasty from the knee joints of patients with RA (n = 8) and OA (n = 6). The synovium was suspended in a bottle containing culture medium and a culture dish at the bottom. Cells were harvested from the dish and analyzed. RESULTS: No significant difference was observed between RA and OA in the harvested cell numbers per g of synovium. However, the variation in the number of cells harvested from each donor was greater for RA than for OA. The harvested cells were multipotent and no difference was observed in the cartilage pellet weight between RA and OA. The surface epitopes of the cells in RA and OA were similar to those of MSCs. CONCLUSION: Mobilization of MSCs from the synovium was demonstrated using a suspended synovium culture model for RA. The harvested cell numbers, chondrogenic potentials, and surface epitope profiles were comparable between the RA and OA models.

[Cartilage/chondrocyte research and osteoarthritis. Current concept and future perspective for diagnosis and treatment of osteoarthritis of the knee.]

Osteoarthritis(OA)of the knee is a joint disease that is primarily affected by articular cartilage and also affected by subchondral bone and meniscus, leading to walking pain and impairing moving ability and as a result, disability. Knee OA is diagnosed by plain radiograph, however, it is not sensitive enough to detect the association between the pathophysiology and symptom of the disease. Treatment target of knee OA is to improve symptom, mainly pain. A conservative treatment is the principle of knee OA treatment, in which the combination of non-pharmacological and pharmacological treatment is primarily recommended. When the conservative treatment is ineffective, surgical treatment could be selected. It is estimated that there are 25 million people with radiographic knee OA in Japan. Recent researches using MRI and biomarkers, in addition to radiograph, have been revealed the precise mechanisms of pathophysiology of knee OA. Recently, it has been suggested that the pathophysiologies associated with pain in knee OA are altered depending upon the severity of disease. It has been expected that the pathophysiology of early stage knee OA will also be clarified.

Return to Play of Rugby Players After Anterior Cruciate Ligament Reconstruction Using Hamstring Autograft: Return to Sports and Graft Failure According to Age.

PURPOSE: To assess return to play and the frequencies of graft failure in rugby players after anterior cruciate ligament (ACL) reconstruction using a hamstring autograft augmented with an artificial ligament and to compare outcomes between rugby players aged <20 and ≥20 years over the long term. METHODS: A consecutive series of 146 rugby players who underwent ACL reconstruction with a hamstring autograft augmented with an artificial ligament were retrospectively reviewed. The study population was further divided into 2 groups aged <20 years and >20 years and compared. RESULTS: Twenty-five patients could not be followed up, and 121 (83%) were evaluated. Most patients (90%, <20 years; 92%, ≥20 years) returned to play after ACL reconstruction. At an average follow-up period of 56.5 months, 16% of the patients sustained an ACL graft rupture. Regarding age, <20 years (n = 58, 48%) and ≥20 years (n = 63, 52%), younger players had a significantly higher failure rate (23% vs 5%, respectively; P = .006) and a shorter time to failure (22.8 ± 13.2 vs 35.4 ± 15.4 months, respectively; P = .006) than older players. CONCLUSIONS: Rugby players were likely to return to play after ACL reconstruction with a hamstring autograft. However, there was a higher risk of graft failure in younger players than in older players. On the basis of this study, we conclude that the hamstring autograft may not be an appropriate graft source to use in a younger active population, including rugby players. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Preoperative timed single leg standing time is associated with the postoperative activity of daily living in aged disabled patients with end-stage knee osteoarthritis at six-months after undergoing total knee arthroplasty.

OBJECTIVES: The aim of the present study was to investigate the effect size (ES) of total knee arthroplasty (TKA) for the symptoms and lower limb function and identify preoperative factor(s) associated with the post-operative activity of daily living (ADL) in aged patients with end-stage knee OA undergoing TKA. METHODS: Fifty-nine aged patients with end-stage knee OA (mean age: 74.6 years) were enrolled in this study. The symptoms and lower limb function of the patients were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM), the timed up and go (TUG) test and timed single-legged stance test with eyes open (TSLS) before and after six months from the operation. RESULTS: While the ES of TKA for the improvement of pain was 2.83, the ES of TKA for the improvement of ADL, TUG and TSLS were 1.30, 0.59, and 0.49, respectively. While the post-operative ADL score was not associated with the preoperative ADL or pain scores, it was associated with the preoperative TUG and TSLS scores. A multiple regression analysis revealed that the one preoperative factor associated with the postoperative ADL was the TSLS. CONCLUSION: The preoperative TSLS is associated with the postoperative ADL in aged disabled patients with end-stage knee OA.

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.