Conservative Treatment Using Platelet-Rich Plasma for Acute Anterior Cruciate Ligament Injuries in Highly Active Patients: A Retrospective Survey.

Background The recommended treatment for anterior cruciate ligament (ACL) injuries in active, sports-oriented patients is reconstructive surgery in order to regain stability and prevent secondary meniscal injuries. However, ACL reconstruction requires a long recovery period and poses issues such as decreased muscle strength due to tendon harvesting and postoperative osteoarthritis (OA) progression, thereby raising significant expectations for the advancement of conservative treatments. Recent studies have shown that platelet-rich plasma (PRP) therapy, which utilizes the tissue repair-promoting property of platelets, is effective for ACL injuries. Methods We administered PRP therapy within six weeks after ACL injury in patients who expressed the desire for an early return to sports through conservative care. After the treatment, patients wore a simple brace that limited deep flexion but placed no restrictions on weight bearing. Four months was the standard goal established for returning to pre-injury condition, and, depending on the target level, timing, and knee condition, we adjusted the additional PRP treatments and rehabilitation approach, gradually authorizing the patients' return to sport. We assessed the ligament repair status by magnetic resonance imaging (MRI) just before the full return to sports. A retrospective survey was conducted to evaluate the status of ligament repair and the condition of return-to-sport in patients with ACL injuries who underwent conservative treatment using PRP. Results The average patient age was 32.7 years and the average treatment was 2.8 PRP sessions. MRI evaluations confirmed that ligament continuity was regained in all cases. All the patients returned to their pre-injury level (Tegner Activity Scale 7.0) in an average of 139.5 days, but there was one instance of re-rupture following the return to sports. Conclusion All patients with ACL injury who underwent PRP therapy regained ligament continuity and returned to sport successfully with only one case of re-rupture.

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.

Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions.

The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169+ osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80+CD38+ M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.

Poor Accuracy of Intraoperation Medial Proximal Tibial Angle Measurement Compared to Alignment Rod Methods in Open-Wedge High Tibial Osteotomy for Medial Knee Osteoarthritis.

The alignment rod is widely used as an index for intraoperative alignment but alignment error is inevitable. The purpose of this study was to verify the accuracy of lower limb alignment correction by measurement of mechanical medial proximal tibial angle (MPTA) as an index in open-wedge high tibial osteotomy (OWHTO). This study was retrospective case series. This study involved 152 patients undergoing OWHTO for primary medial osteoarthritis. Alignment rod or MPTA measurement board was used as an index of optimal correction in OWHTO. Alignment rod was used from October 2013 to May 2017, and MPTA measurement board was used from June 2017 to April 2020. The correction using an alignment rod was that the weight-bearing line ratio (WBLR) passed through 62.5% of the tibial plateau which was defined as Fujisawa's point under intraoperative fluoroscopy (A rod group). The correction using MPTA measurement board was aligning the intraoperative MPTA to the preplanned angle (MPTA group). Preplanned optimal alignment was defined as Fujisawa's point in all patients. Knee injury and osteoarthritis outcome measure (KOOS), Knee Society scoring system objective knee score (KSS), 3-m timed up-and-go test (TUG), single-limb standing test (SLS), and isometric muscle strength of quadriceps and hamstrings were assessed as clinical results. WBLR, MPTA, joint-line convergence angle (JLCA), and joint-line obliquity (JLO) were assessed as radiological results preoperatively and at 1 year after surgery. The clinical and radiological results after OWHTO were compared with both groups. Postoperative WBLR in A rod group was closer to the target alignment (Fujisawa's point: 62.5) than in the MPTA group at all stage (A rod group vs. MPTA group: 63.1 vs. 54.6 at 6 months; 62.0 vs. 53.4 at 1 year; p < 0.001). There were no significant differences in the clinical results between both groups. The intraoperative measurement of medial proximal tibial angle has a risk of undercorrection after OWHTO. His study is a retrospective case series and reflects level of evidence IV.

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.

Study protocol for a randomised placebo controlled trial of platelet-rich plasma injection to prevent post-traumatic knee osteoarthritis after anterior cruciate ligament reconstruction.

INTRODUCTION: The elevated cytokine levels in patients suffering from anterior cruciate ligament (ACL) rupture may lead to acute post-traumatic arthritis (APTA) and post-traumatic osteoarthritis (PTOA). Due to its chondrogenerative and anti-inflammatory effect, platelet-rich plasma (PRP) therapy is expected to show a positive outcome in APTA and PTOA. The proposed trial aims to quantitatively measure the efficacy of PRP injection in arresting post-traumatic cartilage degeneration among patients after ACL reconstruction. METHODS AND ANALYSIS: This will be a single-blind, randomised, prospective, controlled clinical trial designed following the Consolidated Standards of Reporting Trials guidelines. After ACL reconstruction, 80 patients will be randomised to receive either leucocyte-poor PRP injection after joint aspiration or a placebo control group receiving only joint aspiration. Participants (age 20-49 years) will be those who have undergone ACL reconstruction within the past 2 weeks with a body mass index<35 and Kellgren Lawrence osteoarthritis grade<2. The primary outcome will include MRI-T2 values of knee cartilage at 6 months. The secondary outcomes will include pain assessment by Visual Analogue Scale, Knee injury and Osteoarthritis Outcome Score, blood and urine test, physical findings, measurements for muscle strength and joint stability. ETHICS AND DISSEMINATION: The study was approved by The Independent Ethics Committee for Clinical Trials of the Japanese Association for the Promotion of State-of-the-Art Medicine. Results of the trial and each of the outcomes will be shared via conferences and publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTb030200391.

Expression and regulation of recently discovered hyaluronidases, HYBID and TMEM2, in chondrocytes from knee osteoarthritic cartilage.

Destruction of articular cartilage in osteoarthritis (OA) is initiated by depletion of the hyaluronan (HA)-aggrecan network, followed by degradation of the collagen fibrils. Previously, we reported the implications of HA-binding protein involved in HA depolymerization (HYBID), alias cell migration-inducing protein (CEMIP) and KIAA1199, for HA degradation. However, transmembrane protein 2 (TMEM2), which is ~ 50% homologous to HYBID, was discovered as another hyaluronidase, but their expression and regulation by OA chondrocytes remain elusive. Here we report that the absolute mRNA copy numbers of HYBID are significantly (7.1-fold) higher in OA cartilage than normal cartilage, whereas TMEM2 levels are not different between the groups. HA-degrading activity of cultured OA chondrocytes disappeared by siRNA-mediated knockdown of HYBID, but not TMEM2. HYBID expression was significantly up-regulated by treatment with interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α) and additively increased by the combined treatment. No significant changes in the TMEM2 expression were seen by the factors examined. IL-1α remarkably enhanced IL-6 production and increased HYBID expression when soluble IL-6 receptor was supplemented. These results demonstrate that in stark contrast to the constitutive expression of TMEM2 and its negligible HA-degrading activity, HYBID is overexpressed in OA cartilage and up-regulated by IL-6 and TNF-α in OA chondrocytes.

Yields of mesenchymal stromal cells from synovial fluid reflect those from synovium in patients with rheumatoid arthritis.

The yield of primary synovial mesenchymal stromal cells (MSCs) from synovium of patients with rheumatoid arthritis (RA) is highly variable, but cell transplantation therapy with autologous synovial MSCs requires accurate prediction of the synovial MSC yield per synovium weight. Here, we determined whether the yield of synovial fluid MSCs might predict the ultimate yield of primary MSCs from the synovium of RA knees. Synovial fluid and synovium were harvested during total knee arthroplasty from the knee joints of 10 patients with RA. Synovial fluid (1.5 mL) was diluted fourfold and plated equally into six 60 cm2 dishes. Nucleated cells from digested synovium were similarly plated at 1 × 104 cells in 6 dishes. All dishes were cultured for 14 days and analyzed for MSC yields and properties, including in vitro chondrogenesis. The cultured synovial cell number was correlated with the cultured synovial fluid cell number (n = 10, R2 = 0.64, p < 0.01). Synovial fluid cells formed cell colonies and showed MSC-like surface epitopes and multi-differentiation potential. However, the cartilage pellet weight indicated a greater chondrogenic potential of the synovial MSCs (n = 8). The primary MSC yields from synovial fluid and synovium were correlated, indicating that the synovial fluid MSC yield can predict the ultimate synovial MSC yield.

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.

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.

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.

Low bone mineral density due to secondary hyperparathyroidism in the GlatmTg(CAG-A4GALT) mouse model of Fabry disease.

Low bone mineral density (BMD)-diagnosed as osteoporosis or osteopenia-has been reported as a new characteristic feature of Fabry disease; however, the mechanism underlying the development of low BMD is unknown. We previously revealed that a mouse model of Fabry disease [GlatmTg(CAG-A4GALT)] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca2+ reabsorption and hypercalciuria. Here, we investigated bone metabolism in GlatmTg(CAG-A4GALT) mice without marked glomerular or proximal tubular damage. Low BMD was detected by 20 weeks of age via micro-X-ray-computed tomography. Bone histomorphometry revealed that low BMD results by accelerated bone resorption and osteomalacia. Plasma parathyroid hormone levels increased in response to low blood Ca2+-not plasma fibroblast growth factor 23 (FGF-23) elevation-by 5 weeks of age and showed progressively increased phosphaturic action. Secondary hyperparathyroidism developed by 20 weeks of age and caused hyperphosphatemia, which increased plasma FGF-23 levels with phosphaturic action. The expression of 1α-hydroxylase [synthesis of 1α,25(OH)2D3] in the kidney did not decrease, but that of 24-hydroxylase [degradation of 1α,25(OH)2D3] decreased. Vitamin D deficiency was ruled out as the cause of osteomalacia, as plasma 1α,25(OH)2D3 and 25(OH)D3 levels were maintained. Results demonstrate that secondary hyperparathyroidism due to mTAL impairment causes accelerated bone resorption and osteomalacia due to hyperphosphaturia and hypercalciuria, leading to low BMD in Fabry model mice.

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.

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 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.

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.

Serum interleukin 6 levels are associated with depressive state of the patients with knee osteoarthritis irrespective of disease severity.

This cross-sectional study investigated the prevalence of depressive state and association between depressive state and serum interleukin (IL)-6 levels in knee osteoarthritis (OA) patients. A total of 115 painful knee OA patients were enrolled and divided into two groups according to the radiographic OA severity. Pain was evaluated using a visual analog scale (VAS). Depressive state was assessed by the self-rating depression scale (SDS). Serum IL-6 levels were also measured. Pearson's correlation coefficient was used to assess the correlation between the variants tested, and logistic regression analysis was used to identify factors associated with the depressive state. Fifty-two percent of the patients had an SDS score of ≥ 40, which is indicative of the depressive state. The pain VAS score (r = 0.22, p = 0.02) and serum IL-6 level (r = 0.31, p < 0.01) were independently associated with the SDS score of all early-stage knee OA patients (Kellgren-Lawrence [K/L] grade 2). However, only the serum IL-6 level was independently associated with the SDS scores of advanced-stage knee OA patients (K/L grades 3 and 4, r = 0.36, p < 0.01). A logistic regression analysis revealed that serum IL-6 level was the variable for the SDS score [odds ratio 1.41 (95% confidence interval 1.03-1.94, p < 0.03)]. Approximately half of the knee OA patients were found to be in the depressive state, and their serum IL-6 levels to be associated with the depressive state, irrespective of OA severity.

Yields and chondrogenic potential of primary synovial mesenchymal stem cells are comparable between rheumatoid arthritis and osteoarthritis patients.

BACKGROUND: Mesenchymal stem cells derived from the synovial membrane (synovial MSCs) are a candidate cell source for regenerative medicine of cartilage and menisci due to their high chondrogenic ability. Regenerative medicine can be expected for RA patients with the inflammation well-controlled as well as OA patients and transplantation of synovial MSCs would also be a possible therapeutic treatment. Some properties of synovial MSCs vary dependent on the diseases patients have, and whether or not the pathological condition of RA affects the chondrogenesis of synovial MSCs remains controversial. The purpose of this study was to compare the properties of primary synovial MSCs between RA and OA patients. METHODS: Human synovial tissue was harvested during total knee arthroplasty from the knee joints of eight patients with RA and OA respectively. Synovial nucleated cells were cultured for 14 days. Total cell yields, surface markers, and differentiation potentials were analyzed for primary synovial MSCs. RESULTS: Nucleated cell number per 1 mg synovium was 8.4 ± 3.9 thousand in RA and 8.0 ± 0.9 thousand in OA. Total cell number after 14-day culture/1 mg synovium was 0.7 ± 0.4 million in RA and 0.5 ± 0.3 million in OA, showing no significant difference between in RA and OA. Cells after 14-day culture were mostly positive for CD44, CD73, CD90, CD105, negative for CD45 both in RA and OA. There was no significant difference for the cartilage pellet weight and sGAG content per pellet between in RA and OA. Both oil red O-positive colony rate and alizarin red-positive colony rate were similar in RA and OA. CONCLUSIONS: Yields, surface markers and chondrogenic potential of primary synovial MSCs in RA were comparable to those in OA. Synovium derived from RA patients can be the cell source of MSCs for cartilage and meniscus regeneration.