Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma.

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), gender (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

Immune evasion in lung metastasis of leiomyosarcoma: upregulation of EPCAM inhibits CD8+ T cell infiltration.

BACKGROUND: Leiomyosarcomas are among the most common histological types of soft tissue sarcoma (STS), with no effective treatment available for advanced patients. Lung metastasis, the most common site of distant metastasis, is the primary prognostic factor. We analysed the immune environment targeting lung metastasis of STS to explore new targets for immunotherapy. METHODS: We analysed the immune environment of primary and lung metastases in 38 patients with STS using immunohistochemistry. Next, we performed gene expression analyses on primary and lung metastatic tissues from six patients with leiomyosarcoma. Using human leiomyosarcoma cell lines, the effects of the identified genes on immune cells were assessed in vitro. RESULTS: Immunohistochemistry showed a significant decrease in CD8+ cells in the lung metastases of leiomyosarcoma. Among the genes upregulated in lung metastases, epithelial cellular adhesion molecule (EPCAM) showed the strongest negative correlation with the number of CD8+ cells. Transwell assay results showed that the migration of CD8+ T cells was significantly increased in the conditioned media obtained after inhibition or knock down of EPCAM. CONCLUSIONS: EPCAM was upregulated in lung metastases of leiomyosarcoma, suggesting inhibition of CD8+ T cell migration. Our findings suggest that EPCAM could serve as a potential novel therapeutic target for leiomyosarcoma.

Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization.

Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFPTG ; Postn-/- mice and chimeric mice with Col1a2-GFPTG ; tdTomatoTG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.

Geriatric nutritional risk index as a predictor for surgical site infection in malignant musculoskeletal tumours of the trunk.

BACKGROUND AND OBJECTIVE: Surgical site infection (SSI) is common in surgery for malignant musculoskeletal tumours, specifically those arising from the trunk. In this study, we investigated the risk factors for SSI after resection of musculoskeletal tumours of the trunk. METHODS: This retrospective observational study included 125 patients (72 males, 53 females) with musculoskeletal tumours of the trunk in our hospital from 1 April 2008 to 31 August 2023. The incidence of SSI and its risk factors were investigated. RESULTS: SSI was observed in 26% (32/125), and the median time to SSI was 22 days. On multivariate analysis, the following were identified as risk factors for SSI: tumours arising caudal to Jacoby's line (hazard ratio [HR] 4.04; P = .0107), soft tissue reconstruction (HR 3.43; P = .0131), and low Geriatric Nutritional Risk Index (GNRI) (HR 0.96; P = .0304). Patients were classified into two risk categories based on GNRI scores: the risk group (GNRI ≤98) and no risk group (>98). The risk group showed a significantly lower overall noninfection survival rate (P = .023). CONCLUSION: Tumours arising caudal to Jacoby line, soft tissue reconstruction, and lower GNRI were risk factors for SSI. Preoperative and postoperative nutritional interventions should be considered to improve GNRI.

Rare presentation of a primary intraosseous glomus tumor in the humerus of a teenager.

A glomus tumor is a benign mesenchymal tumor comprised of cells that resemble the perivascular modified smooth muscle cells of the glomus body. Glomus tumors typically appear in the superficial lesions of the soft tissue in the extremities, such as the subungual region. However, their occurrence in the bone is rare, with only about 30 cases reported to date. Half of these cases involved the distal phalanges of the fingers or toes, with only three reported cases involving the long bones. Here, we present the first case, a primary glomus tumor in the humerus of a 14-year-old female. An osteolytic and cystic lesion was detected after a pathological fracture occurred during exercise. Despite the tumor's large size, no pathological findings indicated malignancy. The fracture healed through conservative treatment, while the tumor was effectively managed with curettage. Appropriate medical care can be provided to patients by focusing on pathological findings.

Can necrotic depth be a substitute of necrotic volume to predict collapse progression in osteonecrosis of the femoral head?

OBJECTIVE: Although some patients may experience collapse progression while others may not in post-collapse osteonecrosis of the femoral head (ONFH) with a necrotic lesion located within the weight-bearing part of the acetabulum (Type B/C1), few studies have focused on the natural course after collapse. This study aimed to clarify the correlation between necrotic volume (NV) and necrotic depth (ND) in predicting collapse progression in patients with post-collapse ONFH Type B/C1. MATERIALS AND METHODS: We retrospectively reviewed 54 hips with post-collapse ONFH Type B/C1 from 52 consecutive patients who were conservatively followed up for more than 1 year. We measured the amount of femoral head collapse using biplane radiographs at each follow-up period, and produced Kaplan-Meier survival curves with collapse progression (≥ 1 mm) as the endpoint. We compared NV and ND, which were calculated as the ratio of the distance from the articular surface of the femoral head to the deepest point of a necrotic lesion to the femoral head diameter in the mid-coronal slice of T1-weighted magnetic resonance imaging (MRI). RESULTS: We observed collapse progression in 31 hips (57.4%). The NV and ND were significantly greater in hips with collapse progression than in those without collapse progression (p = 0.0127 and 0.0047, respectively). Necrotic volume was significantly correlated with ND　(rs = 0.56, p < 0.0001). CONCLUSION: This study suggests that necrotic depth on the mid-coronal slice of T1-weighted MRI can be a substitute for necrotic volume to predict collapse progression in ONFH Type B/C1.

Low-grade central osteosarcoma with extraosseous dedifferentiation: a rare case.

Low-grade central osteosarcoma (LGCOS), which arises from the intramedullary cavity of the metaphysis of long bones, occasionally exhibits extraosseous spread. Approximately 10-30% of patients with LGCOS exhibit dedifferentiation, but it is rare to experience a primary tumor with a dedifferentiated component. A 38-year-old female patient presented with right knee pain for two months. Imaging studies revealed a bone mass with extraosseous involvement. Wide resection was performed, and pathologic examination led to the diagnosis of LGCOS with a dedifferentiated extraosseous lesion. A single defect in the bone cortex constituted the boundary between the low- and high-grade components. The extraosseous high-grade component included more tumor cells with p53 overexpression and more murine double minute 2 (MDM2) copies compared with the low-grade component. These genetic mutations and copy number alterations can be associated with malignant transformation of LGCOS.

Family History of Developmental Dysplasia of the Hip is a Risk Factor for the Progression of Hip Osteoarthritis.

BACKGROUND: Developmental dysplasia of the hip (DDH) is considered to have genetic predisposition and presents many intrafamilial occurrences. However, there is no report that evaluates the effect of DDH family history on the progression after the onset of hip osteoarthritis (OA). METHODS: Medical interviews about detailed clinical information including family history were conducted on 298 consecutive patients who had undergone surgery for OA due to DDH. Clinical or radiographic items that are associated with the severity of DDH (total hip arthroplasty [THA], involvement of bilateral DDH, onset age of hip pain, and three radiological indices of DDH: center-edge angle, sharp angle, and acetabular roof obliquity) were collected and evaluated in multivariate analyses for their associations with DDH family history in a qualitative or quantitative manner. Survival time analyses for THA as the endpoint was also performed to evaluate the effects of DDH family history on the progression of OA. RESULTS: The DDH family history showed significant associations with bilateral involvement of DDH (odds ratio = 2.09 [95% confidence interval {CI} 1.05 to 4.16]; P = .037), early onset of hip pain (P = .0065), and radiological severity of DDH (P = .016). The DDH family history showed a significant association with undergoing THA (odds ratio = 2.25 [95% CI 1.09 to 4.66]; P = .029), further supported by the Cox regression analyses (hazards ratio = 1.56 [95% CI 1.15 to 2.11]; P = .0044). CONCLUSION: A DDH family history is a risk factor for the progression of hip OA. Stronger genetic predisposition to DDH leads to faster onset and progression of hip OA.

Effects of the location of both anterior and lateral boundaries of the necrotic lesion on collapse progression in osteonecrosis of the femoral head.

BACKGROUND: The location of the lateral boundary of the necrotic lesion to the weight-bearing portion of the acetabulum (Type classification) is an important factor for collapse in osteonecrosis of the femoral head (ONFH). Recent studies also reported the significance of the location of the anterior boundary of the necrotic lesion on the occurrence of collapse. We aimed to assess the effects of the location of both anterior and lateral boundaries of the necrotic lesion on collapse progression in ONFH. METHODS: We recruited 55 hips with post-collapse ONFH from 48 consecutive patients, who were conservatively followed for more than one year. Using a plain lateral radiograph (Sugioka's lateral view), the location of the anterior boundary of the necrotic lesion to the weight-bearing portion of the acetabulum was classified as follows: Anterior-area I (two hips) occupying the medial one-third or less; Anterior-area II (17 hips) occupying the medial two-thirds or less; and Anterior-area III (36 hips) occupying greater than the medial two-thirds. The amount of femoral head collapse was measured by biplane radiographs at the onset of hip pain and each follow-up period, and Kaplan-Meier survival curves with collapse progression (≥1 mm) as the endpoint were produced. The probability of collapse progression was also assessed by the combination of Anterior-area and Type classifications. RESULTS: Collapse progression was observed in 38 of the 55 hips (69.0%). The survival rate of hips with Anterior-area III/Type C2 was significantly lower. Among hips with Type B/C1, collapse progression occurred more frequently in hips with Anterior-area III (21 of 24 hips) than in hips with Anterior-area I/II (3 of 17 hips, P < 0.0001). CONCLUSIONS: Adding the location of the anterior boundary of the necrotic lesion to Type classification was useful to predict collapse progression especially in hips with Type B/C1.

Joint-preserving effect and patient-reported outcomes of transtrochanteric curved varus osteotomy for osteonecrosis of the femoral head.

BACKGROUND: This study assessed the hip survival rate and patient-reported outcome measures (PROMs) of transtrochanteric curved varus osteotomy (CVO) for osteonecrosis of the femoral head (ONFH) compared with those of conservative management. METHODS: The CVO group comprised 32 consecutive patients (39 hips) who underwent CVO for ONFH between 2000 and 2011. The conservative group consisted of 36 consecutive patients (37 hips) who were managed conservatively for at least 1 year after collapse and who had ONFH classified by the Japanese Investigation Committee of Health and Welfare as type B or C1, for which CVO is indicated. Kaplan-Meier analysis of hip survival used any ONFH-related therapeutic surgery as the endpoint. PROMs were evaluated for all patients with surviving hips and radiographs available at the latest follow-up. RESULT: The 10-year hip survival rate in the CVO group was 86.7%, which was significantly higher than the 51.0% 5-year survival rate in the conservative group (p < 0.0001). The Oxford Hip Score and UCLA Activity Score were significantly better in the CVO group without joint space narrowing than in the conservative group, with no significant differences between the CVO group with joint space narrowing and the conservative group. CONCLUSION: CVO could preserve hip joints more effectively than conservative follow-up after collapse, although the presence of joint space narrowing could reduce satisfaction levels even in patients with long-term hip survival.

Predictors of physical activity recovery after total hip arthroplasty: a prospective observational study.

PURPOSE: Little is known about the changes and the factors in physical activity as following total hip arthroplasty (THA). There are potential discrepancies between subjective and objective measurements of physical activity. Thus, our porpose is to compare objective and subjective measurements of activity levels in patients undergoing THA preoperatively, three months and one year following surgery, and investigated the factors that predicts the objective activity level after THA. METHODS: This prospective observational study included 42 patients with unilateral symptomatic hip osteoarthritis who underwent THA. The objective activity level (step counts, sit-to-stands, and upright time) by using a tri-axial accelerometer, PRO (Oxford hip score; OHS and University of California, Los Angeles activity score; UCLA score), and muscle volume around the hip joint by using preoperative computed tomography were measured. RESULTS: The number of steps, OHS, and UCLA score before, at three months, and one year after THA averaged 5092, 6532, and 6545 steps, 30.3, 43.0, and 44.2 points, and 3.4, 4.8, and 4.6 points, respectively, with significant postoperative increases (P < 0.05). No significant difference was found between three months and one year postoperatively. In multivariate analysis, younger age and higher preoperative contralateral gluteal medius volume were the predictors of higher postoperative step counts (P < 0.05). CONCLUSIONS: Physical activity, including step counts, OHS, and UCLA score increased significantly until three months after unilateral THA. Early surgical intervention before contralateral muscle declines and preoperative rehabilitation including contralateral side may additionally improve postoperative activity levels.

Small change in the arithmetic hip-knee-ankle angle during unicompartmental knee arthroplasty improves early postoperative functional outcomes.

INTRODUCTION: The optimal lower-limb alignment after unicompartmental knee arthroplasty (UKA) remains controversial. This study aimed to investigate the optimal lower-limb alignment for functional improvement in the early post-UKA period. We hypothesized that a small change (Δ) in the arithmetic hip-knee-ankle (aHKA) angle during surgery would result in better postoperative knee function. MATERIALS AND METHODS: This single-centered, retrospective study analyzed 91 patients (91 knees) who underwent UKA from April 2021 and December 2022. Preoperative and postoperative standing whole-leg radiographs were used to evaluate the mechanical HKA angle and aHKA angle. The aHKA angle was calculated from the medial proximal tibial angle (MPTA) and lateral distal femoral angle (LDFA). We defined restored aHKA angle as a postoperative aHKA angle within ± 3° of the preoperative aHKA angle. Functional improvement was evaluated using the preoperative and one-year postoperative Knee Society Scoring 2011 (KSS 2011). A multivariate regression analysis was performed to investigate the optimal lower-limb alignment for functional improvement. RESULT: Postoperative restored aHKA angle (p = 0.020) was the only significant factor for improved KSS 2011 scores. Postoperative restored aHKA angle was obtained in 64 patients (70%). ΔMPTA (p < 0.001) and ΔLDFA (p = 0.037) were significant factors associated with a postoperative restored aHKA angle. CONCLUSIONS: UKA restores the native knee, including resurfacing constitutional alignment and medial collateral ligament tension. Minimal change in the aHKA angle during UKA improves the functional outcomes of the knee during the early postoperative period, consistent with the minimally invasive surgical concept of UKA.

Is there a reduction in hip destruction under a treat-to-target strategy in patients with rheumatoid arthritis?

OBJECTIVES: The treatments for rheumatoid arthritis (RA) have been greatly improved, and the tight control of disease activity yields superior clinical outcomes. This study aimed to elucidate the accompanying changes in hip destruction following the implementation of a treat-to-target strategy for patients with RA. METHODS: We extracted 190 hips over two periods, i.e. the early period (1998-2003) and the late period (2013-19), with 103 and 87 hips, respectively. The observed rheumatic changes, such as inward migration, upward migration, and femoral head collapse, were quantitatively evaluated, while osteoarthritic changes, such as the formation of a capital drop, were investigated from radiographs before primary total hip arthroplasty. RESULTS: A comparison of the two periods' data showed that the degree of inward migration (-3.44 vs. -7.45 mm; P < .001) and upward migration (+4.3 vs. +0.95 mm; P < .001) significantly decreased in the late-period group. The collapse of the femoral head was not significantly different. The incidence of capital drops was significantly higher in the late-period group (7.8% vs. 27.5%; P < .001). CONCLUSIONS: The degree of inward and upward migration representative of rheumatic changes reduced, whereas the frequency of capital drops as osteoarthritic changes increased during the late period.

Risk factor analysis of vertebral fractures requiring surgery in patients with ankylosing spondylitis.

OBJECTIVES: This study aimed to determine the risk factors for vertebral fractures requiring surgery in patients with ankylosing spondylitis (AS). METHODS: We included 60 patients with AS diagnosed by using the modified New York criteria and who were treated in our department from April 2004 to March 2019. We evaluated age, sex, disease duration, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ankylosed sacroiliac joint, bamboo spine, number of ankylosed vertebrae, and treatment (nonsteroidal antiinflammatory drugs (NSAIDs)), prednisolone (PSL), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), spine surgery for vertebral fracture) at the final follow-up of the nonsurgical group and the preoperative follow-up of the surgical group. RESULTS: At the final follow-up, the mean age was 49 years, 46 patients (75%) were male, and the mean disease duration was 27 years. Additionally, 8 (13.3%) and 43 patients (71%) underwent surgical and medical treatments, respectively. The group of surgery for vertebral fracture had significantly higher CRP levels, which was also significantly associated with vertebral fracture surgery by multivariate analysis. CONCLUSIONS: CRP was identified as a risk factor for vertebral fractures requiring surgery. Control of systemic inflammation in patients with AS may reduce the risk of vertebral fractures requiring surgery.

Prognostic value of nuclear morphometry in myxoid liposarcoma.

Myxoid liposarcoma (MLS) accounts for 20%-30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization/International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software-based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high-nuclear-grade group according to the modified Fuhrman grading system exhibited a significantly poor disease-free survival (hazard ratio: 4.43; 95% confidence interval: 0.9-22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high-grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density) but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high-grade group significantly expressed the cell cycle-related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

Extensive analysis of 59 sarcoma-related fusion genes identified pazopanib as a potential inhibitor to COL1A1-PDGFB fusion gene.

Sarcomas are malignant mesenchymal tumors that are extremely rare and divergent. Fusion genes are involved in approximately 30% of sarcomas as driver oncogenes; however, their detailed functions are not fully understood. In this study, we determined the functional significance of 59 sarcoma-related fusion genes. The transforming potential and drug sensitivities of these fusion genes were evaluated using a focus formation assay (FFA) and the mixed-all-nominated-in-one (MANO) method, respectively. The transcriptome was also examined using RNA sequencing of 3T3 cells transduced with each fusion gene. Approximately half (28/59, 47%) of the fusion genes exhibited transformation in the FFA assay, which was classified into five types based on the resulting phenotype. The sensitivity to 12 drugs including multityrosine kinase inhibitors was assessed using the MANO method and pazopanib was found to be more effective against cells expressing the COL1A1-PDGFB fusion gene compared with the others. The downstream MAPK/AKT pathway was suppressed at the protein level following pazopanib treatment. The fusion genes were classified into four subgroups by cluster analysis of the gene expression data and gene set enrichment analysis. In summary, the oncogenicity and drug sensitivity of 59 fusion genes were simultaneously evaluated using a high-throughput strategy. Pazopanib was selected as a candidate drug for sarcomas harboring the COL1A1-PDGFB fusion gene. This assessment could be useful as a screening platform and provides a database to evaluate customized therapy for fusion gene-associated sarcomas.

C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2 O2 ), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2 O2 , whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2 O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2 O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.

GPR55 contributes to neutrophil recruitment and mechanical pain induction after spinal cord compression in mice.

Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3+ T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis.

Autoreactivity of Peripheral Helper T Cells in the Joints of Rheumatoid Arthritis.

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell-helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vß usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self-MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling.

"Grand-piano sign" as a femoral rotational indicator in both varus and valgus knees: a simulation study of anterior resection surface in total knee arthroplasty.

PURPOSE: The "Grand-piano sign" is a popular indicator of the appropriate rotational alignment of the femoral component during total knee arthroplasty (TKA). The aim of the study was to investigate the shape of the anterior femoral resection surface of varus and valgus knees. METHODS: A cohort of 80 varus knees and 40 valgus knees (hip-knee-ankle angle > 2° for varus and < - 2° for valgus knees) matched for age, sex, height, body weight, and KL grade was made using propensity score matching. Virtual TKA was performed using 3 patterns of components (anterior flange flexion angles of 3°, 5°, and 7°). The anterior femoral resection surface was evaluated for 3 patterns of rotational alignments: parallel to the surgical epicondylar axis (NR, neutral rotation), 3° internal rotation (IR), and 3°external rotation (ER) relative to the surgical epicondylar axis. In each anterior femoral resection surface, the vertical height of medial and lateral condyles was measured, and the ratio of the medial to the lateral height (M/L ratio) was evaluated. RESULTS: The M/L ratio in NR for both varus and valgus knees was 0.57 to 0.64, with no significant difference between the cohorts (p value > 0.05). The M/L ratio showed a similar pattern of increasing at IR and decreasing at ER in both varus and valgus knees. The variation in the M/L ratio with malrotation in valgus knees was smaller than in varus knees. CONCLUSION: During TKA, the anterior femoral resection surface was similar in varus and valgus knees; however, the variation with malrotation was smaller in valgus knees than in varus knees. TKA for valgus knees requires precise surgical technique and careful intraoperative assessment. LEVEL OF EVIDENCE: IV, Case series.