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Purpose Anterior cruciate ligament (ACL) injury induces anterior and rotatory instability of the knee. However, the effect of this instability on the stress distribution in the knee joint in living participants is not clear. The aim of this study was to compare the distribution pattern of subchondral bone density across the proximal tibia in the knees with and without ACL injury, and to investigate the correlation between the distribution patterns of the subchondral bone density and the duration of ACL-deficiency. Methods Radiographic and computed tomography (CT) data pertaining to 20 patients with unilateral ACL injury without combined injury (ACL-deficient group) and 19 nontraumatic subjects (control group) were collected retrospectively. Subchondral bone density of the proximal tibia was assessed using CT-osteoabsorptiometry. Both the medial and lateral compartments of the proximal tibia were divided into three subregions of equal width in the sagittal direction. The percentage of high subchondral bone density areas (HDA%) in each subregion was quantitatively analyzed. Results HDA% of the posteromedial region was significantly higher in the ACL-deficient group (mean: 21.6%) than in the control group (14.7%) (p = 0.002). In contrast, HDA% of the anteromedial region was significantly lower in the ACL-deficient group (9.4%) than in the control group (15.3%) (p = 0.048). The logarithm of the time elapsed from ACL injury to CT examination showed a significant correlation with HDA% in the posteromedial region (p = 0.032). Conclusions Subchondral bone density in the posteromedial region significantly increased after ACL injury and correlated with the duration of ACL-deficiency in semi-log manner in meniscus intact knees. The increase in stress on the posteromedial region after ACL injury, which induces a change in the subchondral bone density, justifies early ACL reconstruction after ACL injury.

Objective Accurate analysis to quantify cartilage morphology is critical for evaluating degenerative conditions in osteoarthritis (OA). Three-dimensional (3D) optical scanning provides 3D data for the entire cartilage surface; however, there is no consensus on how to quantify it. Our purpose was to validate a 3D method for evaluating spatiotemporal alterations in degenerative cartilages in a rabbit OA model by analyzing their curvatures at various stages of progression. Design Twelve rabbits underwent anterior cruciate ligament transection (ACLT) unilaterally and were divided into 4 groups: 4 weeks control, 4 weeks OA, 8 weeks control, and 8 weeks OA. 3D scanning, India ink staining, and histological assessments were performed in all groups. In 3D curvature visualization, the surfaces of the condyles were divided into 8 areas. The standard deviations (SD) of mean curvatures from all vertices of condylar surfaces and subareas were calculated. Results Regarding the site of OA change, curvature analysis was consistent with India ink scoring. The SD of mean curvature correlated strongly with the India ink Osteoarthritis Research Society International (OARSI) score. In curvature histograms, the curvature distribution in OA was more scattered than in control. Of the 8 areas, significant OA progression in the posterolateral part of the lateral condyle (L-PL) was observed at 4 weeks. The histology result was consistent with the 3D evaluation in terms of representative section. Conclusions This study demonstrated that 3D scanning with curvature analysis can quantify the severity of cartilage degeneration objectively. Furthermore, the L-PL was found to be the initial area where OA degeneration occurred in the rabbit ACLT model.

Foreign body granulomas from sutures are more common among non-absorbable sutures compared to absorbable sutures and have been reported as a postoperative complication in a variety of medical fields. However, only a few cases of delayed foreign body reaction have been reported and addressed with orthopedics. We present a patient with systemic lupus erythematosus who developed an infectious suture granuloma that extended to the entire Achilles tendon and was induced by nonabsorbable sutures that were used for open Achilles tendon repair 20 years before. This granuloma was resistant to antibiotic treatment and drainage and required surgical intervention. The tumor was marginally resected, and the continuity of the Achilles tendon was preserved. Histopathological examination detected many suture materials surrounded by xanthochromic necrotic lesions and the lesion was diagnosed as a foreign body granuloma. At 1 year after the operation, the patient did not exhibit exacerbation of infection or recurrence of the tumor, and she became able to walk by herself. To the best of our knowledge, this represents the first report of an infectious delayed foreign body granuloma in autoimmune disorder patient after open Achilles tendon repair. Surgical intervention should be considered, as treatment with conservative therapy such as antibiotics may be difficult.

The objectives of this study were to clarify whether resection of primary tumor in the extremities for patients with metastatic soft-tissue sarcoma (STS) improves survival, and to clarify patient groups for whom primary tumor resection should be considered. Using the surveillance, epidemiology, and end results database, we identified 1453 patients with metastatic STS of the extremities at initial presentation between 1983 and 2016. Of these 1453 patients, 898 patients underwent primary tumor resection (Surgery group), and 555 patients did not (No-surgery group). After adjusting for patient background by propensity score matching, a total of 804 patients were included for analysis. Patients in the Surgery group showed improved survival (cancer-specific survival (CSS) hazard ratio (HR) = 0.59, 95% confidence interval (CI) 0.50–0.71 overall survival rate (OS) HR = 0.60, 95% CI 0.51–0.70). In subclass analysis, patients with high-grade STS, undifferentiated pleomorphic sarcoma, leiomyosarcoma, or synovial sarcoma showed improved survival in the Surgery group (high grade—CSS HR = 0.57, 95% CI 0.45–0.72, OS HR = 0.58, 95% CI 0.48–0.71; undifferentiated pleomorphic sarcoma—CSS HR = 0.60, 95% CI 0.42–0.84, OS HR = 0.61, 95% CI 0.46–0.82; leiomyosarcoma—CSS HR = 0.50, 95% CI 0.33–0.75, OS HR = 0.50, 95% CI 0.35–0.72; synovial sarcoma—CSS HR = 0.46, 95% CI 0.31–0.68, OS HR = 0.43, 95% CI 0.30–0.62). Our results indicated that primary tumor resection in metastatic STS exerts positive impacts on survival. Further clinical research is needed to confirm these results.

Background/Aim: Although smoking history is predictive of poor pulmonary metastasis-free survival (PMFS) in patients with epithelial tumors, the impact of smoking history on PMFS in those with soft-tissue sarcoma (STS) is not known. Patients and Methods: Patients undergoing treatment for STS at our institutes between 2008 and 2017 were enrolled. Patients were excluded if they had metastatic lesion, or had a histopathological classification demonstrating small round-cell sarcoma. The impact of smoking history on PMFS and overall survival was examined with multivariate analysis using a Cox proportional hazards model. Results: A total of 250 patients were retrospectively reviewed. Patients with smoking history had worse PMFS on multivariate analysis (hazard ratio=2.00, 95% confidence interval=1.12-3.60). On the other hand, smoking history did not significantly affect overall survival (hazard ratio=1.26, 95% confidence interval=0.61-2.58). Conclusion: Patients with STS need to be followed-up by frequent clinical assessments if they have a smoking history.

Background:The effect of high tibial osteotomy (HTO) on the stress distribution across the knee joint is not completely understood. Subchondral bone density is considered to reflect the pattern of stress distribution across a joint surface.Purpose:To assess the distribution of subchondral bone density across the proximal tibia in nonarthritic knees and in the knees of patients with osteoarthritis (OA) before and after HTO.Study Design:Cohort study; Level of evidence, 3.Methods:We retrospectively collected radiological and computed tomography data from 16 patients without OA (control group) and 17 patients with OA. Data from the OA group were collected before and 1.5 years after HTO. Subchondral bone density of the proximal tibia was assessed with computed tomography–osteoabsorptiometry. The locations and percentages represented by high-density areas (HDAs) on the articular surface were quantitatively analyzed.Results:The ratio of the HDA of the medial compartment to the total HDA (medial ratio) was significantly higher in the preoperative OA group (mean, 80.1%) than in the control group (61.3%) ( P < .001). After HTO, the medial ratio decreased significantly to 75.1% ( P = .035 in comparison with preoperative values) and was significantly correlated with the hip-knee-ankle angle in both groups: control ( r = −0.551; P = .033) and OA ( r = −0.528; P = .043). The change in medial ratio after HTO was significantly correlated with the change in hip-knee-ankle angle ( r = 0.587; P = .035). In the medial compartment, the HDA in the most lateral region of 4 subregions increased after HTO, but that in 3 medial subregions decreased.Conclusion:In this exploratory study, HTO shifted the HDA of the medial compartment of the proximal tibial articular surface toward the lateral compartment. In contrast, the HDA of the most lateral region of the medial compartment increased after HTO. This change in subchondral bone density may result from the change in stress distribution.

Background Hemarthrosis after total knee arthroplasty (TKA) is a relatively rare complication. Although most cases are effectively treated with conservative therapy, some cases require angiographic embolization or surgical intervention. Angiosarcoma is a rare malignant tumor derived from the vascular endothelium with neovascular hyperplasia and mainly arises in the skin and superficial soft tissue, and less frequently in deep soft tissue and bone. Although malignant neoplasms such as angiosarcoma in the vicinity of orthopedic implants were reported, the causal relationship between development of the malignant tumor and the orthopedic implant is widely debated in the literature. Case presentation We report the case of a 68-year-old female with angiosarcoma that developed in the knee joint 2 years after revision TKA. The patient exhibited severe persistent bleeding, which reached 1000–1400 ml per day for 4 months. Histological analysis of the synovial tissue in the knee joint showed large cells with nuclear atypia. Immunohistochemical staining showed cells that were positive for CD31, CD34, and D2-40, and she was diagnosed with angiosarcoma. The patient underwent an amputation at the level of the thigh, and her general condition immediately improved after the operation. The patient did not exhibit bleeding from the site of amputation, and no local recurrence or distant metastases were detected 1 year after the amputation. Conclusions To the best of our knowledge, this represents the first report of angiosarcoma 2 years after revision TKA. Further careful follow up is needed, given the high-grade malignancy.

Hallux valgus deformity is one of the most common foot and ankle diseases, while brachymetatarsia is a rare foot anomaly with pathological shortening of a metatarsal bone. We present a case of hallux valgus deformity possibly due to second brachymetatarsia. As the hallux valgus was associated with dorsal dislocation of the second toe that made it difficult to evaluate the length of the second toe, the patient was unaware of the second metatarsal shortening until the lengths of the toes compared by manual reposition of the second MTP joint. In this case, proximal osteotomy of the first metatarsal on the hallux valgus and single-stage bone lengthening of the second metatarsal with iliac bone grafting on the second brachymetatarsia were performed. One year after the operation, the callosity of the third toe resolved and the clinical scores were improved. In the case of a hallux valgus deformity with second dorsal dislocation of the toes, surgeons should consider that there are rare cases with second metatarsal shortening. When hallux valgus associated with second brachymetatarsia is diagnosed, second metatarsal lengthening should be considered in addition to hallux valgus surgery.

OBJECTIVE Optineurin (OPTN) is an autophagy adaptor/receptor that acts as an intrinsic negative regulator of osteoclast differentiation. RANKL expressed by rheumatoid arthritis synovial fibroblasts (RASFs) is primarily responsible for the development of bone erosions in patients with RA. The aim of the present study was to explore the role of OPTN in the pathogenesis of joint destruction in RA. METHODS RASFs were left untreated or incubated with tumor necrosis factor (TNF) or interferon-γ (IFNγ), and expression of OPTN by RASFs was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Expression of RANKL and osteoprotegerin (OPG) was evaluated in cultures of OPTN-reduced RASFs with or without TNF or IFNγ treatment. OPTN-reduced RASFs were cocultured with monocytes and stained for tartrate-resistant acid phosphatase (TRAP). IκBα, NF-κB1, and RelA protein levels were measured to evaluate NF-κB signaling. Expression of messenger RNA (mRNA) for matrix metalloproteinase 3 (MMP3), interleukin-6 (IL6), GATA binding protein 3 (GATA3), carbohydrate sulfotransferase 15 (CHST15), hyaluronan synthase 1 (HAS1), and GATA1 was analyzed by RT-qPCR. RESULTS In RASFs incubated with TNF or IFNγ, OPTN expression was up-regulated and RANKL expression was increased, and these effects were further pronounced in OPTN-reduced RASFs (all P < 0.05 versus controls). OPG mRNA levels remained unchanged. Monocytes cocultured with OPTN-reduced RASFs differentiated to a greater extent into TRAP+ multinucleated cells compared to monocytes cocultured with control RASFs (P < 0.05). IκBα degradation and nuclear NF-κB1 expression following TNF treatment were both prolonged in OPTN-reduced RASFs (each P < 0.05 versus controls). MMP3 mRNA levels were up-regulated, while GATA3, CHST15, and HAS1 mRNA levels were down-regulated in OPTN-reduced RASFs (each P < 0.05 versus controls). CONCLUSION OPTN plays a protective role in RA when it is up-regulated in RASFs in the presence of proinflammatory cytokines. Absence of OPTN might worsen RA by generating a joint-destructive state, as indicated by evidence of increased RANKL expression on RASFs and subsequent osteoclast differentiation.

Accumulating evidence suggests that synovitis is associated with osteoarthritic process. Macrophages play principal role in development of synovitis. Our earlier study suggests that interaction between cartilage fragments and macrophages exacerbates osteoarthritic process. However, molecular mechanisms by which cartilage fragments trigger cellular responses remain to be investigated. Therefore, the current study aims at analyzing molecular response of macrophages to cartilage fragments. To this end, we analyzed the transcriptional profiling of murine macrophages exposed to cartilage fragments by RNA sequencing. A total 153 genes were differentially upregulated, and 105 genes were down-regulated in response to cartilage fragments. Bioinformatic analysis revealed that the most significantly enriched terms of the upregulated genes included scavenger receptor activity, integrin binding activity, TNF signaling, and toll-like receptor signaling. To further confirm our results, immunohistochemical staining was performed to detected regulated molecules in synovial tissues of OA patients. In consistence with RNA-seq results, MARCO, TLR2 and ITGα5 were mainly detected in the intima lining layer of synovial tissues. Moreover, blockade of TLR2 or ITGα5 but not Marco using specific antibody significantly reduced production of TNF-α in stimulated macrophages by cartilage fragments. Our data suggested that blocking TLR2 or ITGα5 might be promising therapeutic strategy for treating progressive osteoarthritis.

PurposePatellar resurfacing in total knee arthroplasty (TKA) remains controversial as recent meta-analyses have not shown its clear superiority; however, most authors recommend it because it is associated with less frequent anterior knee pain and need for reoperation. We aimed to clarify the changes in patellar cartilage thickness in no patellar resurfacing TKA using a ceramic femoral component on magnetic resonance imaging (MRI).MethodsBetween 2009 and 2014, 40 consecutive patients (59 knees) were included in this study. All patients underwent TKA using zirconia ceramic femoral implants without patellar resurfacing. Indications for no patellar resurfacing TKA were absence of anterior knee pain, patellar compression pain, and osteoarthritic changes in the patellofemoral joint on plain radiography. The mean postoperative follow-up duration was 81.5 months (range, 25–131 months). Clinical and radiological evaluations were performed preoperatively and 5 years after TKA. Patellar cartilage thickness was evaluated preoperatively and every year for 5 years after TKA using MRI T2-weighted imaging. The patellar cartilage was divided into three regions of interest: medial, central, and lateral. To standardise the variation in patellar thickness among patients, the percent cartilage thickness was calculated.ResultsThe implant’s position was appropriate in all cases. Compared to preoperative scores, 5 years postoperatively, the Japanese Orthopedic Association score and Oxford knee score significantly improved from 52.1 to 84.7; mean tilting angle and congruence angle did not change significantly; mean lateral shift ratio significantly increased from 7.1% to 14.6%; cartilage thickness significantly decreased (P ConclusionThe patellar cartilage thickness decreased to less than half its preoperative level within 5 years after no patellar resurfacing TKA; this would led to clinical problems and conversion to patellar resurfacing.Level of evidenceLevel III.

Background/aim Brain metastasis is a rare condition among patients with soft tissue sarcoma (STS), and its precise incidence remains unclear. The aim of this study was to investigate which patients should be screened for brain metastasis. Patients and methods We identified all patients with STS diagnosed between 2010 and 2015 in the SEER database. Incidence of brain metastasis at initial presentation and higher incidence of brain metastasis by histological subtype were investigated. In addition, risk factors for brain metastasis were examined. Results A total of 26,676 patients were included for analysis, of whom 162 patients (0.6%) had brain metastasis. Alveolar soft part sarcoma (6.3%), malignant hemangioendothelioma (3.1%) and malignant schwannoma (2.6%) showed higher incidence of brain metastasis. Deep-rooted tumor, trunk tumor, and histological high-grade tumor tended to show higher incidence of brain metastasis. Conclusion Risk factors for brain metastasis were deep location, trunk development and histologically high-grade tumor, or specific histological subtypes.

Summary Objective Gangliosides, ubiquitously existing membrane components that modulate transmembrane signaling and mediate cell-to-cell and cell-to-matrix interactions, are key molecules of inflammatory and neurological disorders. However, the functions of gangliosides in the cartilage degradation process remain unclear. We investigated the functional role of gangliosides in cartilage metabolism related to osteoarthritis (OA) pathogenesis. Design We generated knockout (KO) mice by targeting the β1, 4-N-acetylgalactosaminyltransferase (GalNAcT) gene, which encodes an enzyme of major gangliosides synthesis, and the GD3 synthase (GD3S) gene, which encodes an enzyme of partial gangliosides synthesis. In vivo OA and in vitro cartilage degradation models were used to evaluate the effect of gangliosides on the cartilage degradation process. Results The GalNAcT and GD3S KO mice developed and grew normally; nevertheless, OA changes in these mice were enhanced with aging. The GalNAcT KO mice showed significantly enhanced OA progression compared to GD3S mice in vivo. Both GalNAcT and GD3S KO mice showed severe IL-1α–induced cartilage degradation ex vivo. Phosphorylation of MAPKs was enhanced in both GalNAcT and GD3S KOs after IL-1α stimulation. Gangliosides modulated by GalNAcT or GD3S rescued an increase of MMP-13 induced by IL-1α in mice lacking GalNAcT or GD3S after exogenous replenishment in vitro. Conclusion These data show that the deletion of gangliosides in mice enhanced OA development. Moreover, the gangliosides modulated by GalNAcT are important for cartilage metabolism, suggesting that GalNAcT is a potential target molecule for the development of novel OA treatments.

Background: One of the most important limitations of osteochondral autograft transplantation (OAT) is the adverse effect on donor sites in the knee. To decrease the number and/or size of osteochondral defects, we devised a method with biomaterial implantation after OAT. Hypothesis: OAT augmented by ultrapurified alginate (UPAL) gel enhances cartilage repair capacity. Study Design: Controlled laboratory study. Methods: Seventy-five osteochondral defects in rabbits were divided into 3 groups: osteochondral defects with OAT alone, defects with OAT augmented by UPAL gel (combined group), and defects without intervention as controls. Macroscopic and histological evaluations of the reparative tissues were performed at 4 and 12 weeks postoperatively. Histological evaluation of graft cartilage degradation was also performed. To evaluate the effects of UPAL gel on graft healing, repaired bone volumes and osseointegration of the graft were evaluated. Collagen orientation and the mechanical properties of the reparative tissue and graft cartilage were also evaluated qualitatively. Results: The macroscopic and histological evaluations of the combined group were significantly superior to the other groups at 12 weeks postoperatively. Regarding degenerative change of the graft, the histological scores of the combined group were significantly higher than those of the OAT-alone group. The values of repaired subchondral bone volumes and osseointegration of the graft were almost identical in both groups. Collagen orientation and the mechanical properties of the reparative tissue and graft cartilage were significantly better in the combined group than in the other groups. Conclusion: Administration of UPAL gel in OAT enhanced cartilage repair and protected graft cartilage without inhibiting subchondral bone repair and graft survival. Clinical Relevance: OAT augmented by UPAL gel decreases the number and/or size of osteochondral grafts, minimizing the risk of donor site morbidity. This combination technique has the potential to improve clinical outcomes and expand the surgical indications for OAT.

Background: Ultrapurified alginate (UPAL) gel implantation has been demonstrated as effective in cartilage repair for osteochondral defects; however, cell transplantation within UPAL gels would be required to treat larger defects. Hypothesis: The combination of UPAL gel and bone marrow aspirate concentrate (BMAC) would enhance cartilage repair and subchondral bone repair for large osteochondral defects. Study Design: Controlled laboratory study. Methods: A total of 104 osteochondral defects (1 defect per knee) of 52 rabbits were randomly divided into 4 groups (26 defects per group): defects without any treatment (Defect group), defects treated using UPAL gel alone (UPAL group), defects treated using UPAL gel containing allogenic bone marrow mesenchymal stromal cells (UPAL-MSC group), and defects treated using UPAL gel containing BMAC (UPAL-BMAC group). At 4 and 16 weeks postoperatively, macroscopic and histologic evaluations and measurements of repaired subchondral bone volumes of reparative tissues were performed. Collagen orientation and mechanical properties of the reparative tissue were assessed at 16 weeks. Results: The defects in the UPAL-BMAC group were repaired with hyaline-like cartilage with well-organized collagen structures. The histologic scores at 4 weeks were significantly higher in the UPAL-BMAC group (16.9 ± 2.0) than in the Defect group (4.7 ± 1.9; P < .05), the UPAL group (10.0 ± 3.3; P < .05), and the UPAL-MSC group (12.2 ± 2.9; P < .05). At 16 weeks, the score in the UPAL-BMAC group (24.4 ± 1.7) was significantly higher than those in the Defect group (9.0 ± 3.7; P < .05), the UPAL group (14.2 ± 3.9; P < .05), and the UPAL-MSC group (16.3 ± 3.6; P < .05). At 4 and 16 weeks, the macroscopic evaluations were significantly superior in the UPAL-BMAC group compared with the other groups, and the values of repaired subchondral bone volumes in the UPAL-BMAC group were significantly higher than those in the Defect and UPAL groups. The mechanical properties of the reparative tissues were significantly better in the UPAL-BMAC group than in the other groups. Conclusion: The implantation of UPAL gel containing BMAC-enhanced hyaline-like cartilage repair and subchondral bone repair of osteochondral defects in a rabbit knee model. Clinical Relevance: These data support the potential clinical application of 1-step treatment for large osteochondral defects using biomaterial implantation with cell transplantation.

Background: Medial open-wedge high tibial osteotomy (OWHTO) theoretically causes distalization and lateralization of the tibial tuberosity and the patella. Purpose/Hypothesis: The purpose of the study was to identify any changes in the stress distribution of subchondral bone density across the patellofemoral (PF) joint before and after OWHTO through the use of computed tomography (CT) osteoabsorptiometry. We hypothesized that OWHTO would alter the distribution of contact stress in the PF joint. Study Design: Case series; Level of evidence, 4. Methods: A total of 17 patients (17 knees) who underwent OWHTO were enrolled in this study between September 2013 and September 2015. All patients underwent radiologic examination preoperatively and at 1 year postoperatively, and the distribution patterns of subchondral bone density through the articular surface of the femoral trochlea and patella were assessed preoperatively and >1 year postoperatively using CT osteoabsorptiometry. The quantitative analysis of the obtained mapping data focused on location of the high-density area (HDA) through the articular surface of the PF joint. The percentage of HDA at each divided region of the articular surface of the femoral trochlea and the patella was calculated. Results: In the radiologic evaluation, the Blackburne-Peel ratio was significantly reduced ( P < .001) after surgery, and the tilting angle of the patella was significantly decreased ( P < .001). On CT evaluation, the percentage of HDA in the lateral notch and lateral trochlea of the femur and in the medial portion of the lateral facet of the patella increased significantly after OWHTO surgery ( P ≤ .038). Conclusion: OWHTO significantly increased the stress distribution pattern of the lateral trochlea of the femur and the medial portion of the lateral facet of the patella. The procedure significantly lowered the patellar height and significantly decreased the patellar tilting angle after surgery.

Background: One of the most important limitations of osteochondral autograft transplant is the adverse effect on donor sites in the knee. Ultrapurified alginate (UPAL) gel is a novel biomaterial that enhances hyaline-like cartilage repair for articular defects. To avoid the need for knee cartilage autografting when treating osteochondritis dissecans (OCD) of the capitellum, we developed a surgical procedure involving a bone marrow stimulation technique (BMST) augmented by implantation of UPAL gel. Hypothesis: BMST augmented by UPAL gel implantation improves the cartilage repair capacity and provides satisfactory clinical outcomes in OCD of the capitellum. Study Design: Case series; Level of evidence, 4. Methods: A total of 5 athletes with advanced capitellar OCD in the dominant elbow underwent BMST augmented by implantation of UPAL gel. The osteochondral defects were filled with UPAL gel after BMST. At a mean follow-up of 97 weeks, all patients were evaluated clinically and radiographically. Results: At final follow-up, all 5 patients had returned to competitive-level sports, and 4 patients were free from elbow pain. The mean Timmerman-Andrews score significantly improved from 100 to 194 points. Radiographically, all patients exhibited graft incorporation and a normal contour of the subchondral cortex. Magnetic resonance imaging showed that the preoperative heterogeneity of the lesion had disappeared, and the signal intensity had returned to normal. Arthroscopic examinations consistently exhibited improvement in the International Cartilage Regeneration and Joint Preservation Society (ICRS) grade of lesions from 3 or 4 to 1 or 2 in 4 patients at 85 weeks postoperatively. Histologic analysis of biopsy specimens revealed an average total ICRS Visual Assessment Scale II histologic score of 1060. Conclusion: The acellular cartilage repair technique using UPAL gel for advanced capitellar OCD provided satisfactory clinical and radiographic results. The present results suggest that this novel technique is a useful, minimally invasive approach for treating cartilaginous lesions in athletes.

Osteoid osteomas are benign, typically intracortical lesions most often affecting the diaphysis of long bones. Nocturnal pain and characteristic symptoms that are relieved by administration of nonsteroidal anti-inflammatory drugs (NSAIDs) are present and can help in the diagnosis of osteoid osteoma. We report a case of 18-year-old boy with an osteoid osteoma in the olecranon fossa with an atypical clinical manifestation. The initial manifestation was arthritis-like symptoms such as local heat, motion pain rather than pain at rest, and limited range-of-motion. Notably, NSAIDs were not effective at all for relieving his symptoms. Magnetic resonance imaging showed bone marrow edema around the elbow joint. The symptoms were resistant to conservative treatments, and thus, surgical resection was required. Histopathological examination showed that the lesion consisted of woven bones and osteoid tissues that anastomosed with each other. Combined with a tumor size that was less than 2 cm, clinicopathologically, the tumor was diagnosed as an osteoid osteoma. The pain was immediately relieved after the operation, and range-of-motion recovered at 2 months postoperatively. At 1 year after the surgery, the patient did not exhibit recurrence of the tumor or exacerbation of elbow pain and had a full range of elbow motion. Osteoid osteoma should be considered for the differential diagnosis of arthritis of the elbow in patients who are adolescents and young adults, which is the peak age of onset for osteoid osteoma.

Introduction: The ongoing outbreak of novel coronavirus disease 2019 (COVID-19) is a worldwide problem. Although diagnosing COVID-19 in fracture patients is important for selecting treatment, diagnosing early asymptomatic COVID-19 is difficult. We describe herein a rare case of femoral intertrochanteric fracture concomitant with early asymptomatic novel COVID-19. Case presentation: An 87-year-old Japanese woman was transferred to our emergency room with a right hip pain after she fell. She had no fever, fatigue, or respiratory symptoms on admission and within the 14 days before presenting to our hospital, and no specific shadow was detected in chest X-ray. However, chest computed tomography (CT) was performed considering COVID-19 pandemic, and showed ground-glass opacities with consolidation in the dorsal segment of the right lower lung field. Then, qualitative real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) was carried out and turned out to be positive. She was diagnosed right femoral intertrochanteric fracture with concomitant COVID-19 infection. Conservative treatment was applied to the fracture due to infection. After admission, fever and oxygen demand occurred but she recovered from COVID-19. Throughout the treatment period, no cross-infection from the patient was identified in our hospital. Conclusion: This case highlights the importance of considering chest CT as an effective screening method for infection on hospital admission in COVID-19-affected areas, especially in trauma patients with early asymptomatic novel COVID-19.

Periprosthetic osteolysis induced by orthopedic implant-wear particles continues to be the leading cause of arthroplasty failure in majority of patients. Release of the wear debris results in a chronic local inflammatory response typified by the recruitment of immune cells, including macrophages. The cellular mediators derived from activated macrophages favor the osteoclast-bone resorbing activity resulting in bone loss at the site of implant and loosening of the prosthetic components. Emerging evidence suggests that chemokines and their receptors are involved in the progression of periprosthetic osteolysis associated with aseptic implant loosening. In the current study, we investigated the potential role of chemokine C-motif-ligand-1 (XCL1) in the pathogenesis of inflammatory osteolysis induced by wear particles. Expressions of XCL1 and its receptor XCR1 were evident in synovial fluids and tissues surrounding hip-implants of patients undergoing revision total hip arthroplasty. Furthermore, murine calvarial osteolysis model induced by ultra-high molecular weight polyethylene (UHMWPE) particles was used to study the role of XCL1 in the development of inflammatory osteolysis. Mice received single injection of recombinant XCL1 onto the calvariae after implantation of particles exhibited significantly greater osteolytic lesions than the control mice. In contrast, blockade of XCL1 by neutralizing antibody significantly reduced bone erosion and the number of bone-resorbing mature osteoclasts induced by UHMWPE particles. In consistence with the results, transplantation of XCL1-soaked sponge onto calvariae caused osteolytic lesions coincident with excessive infiltration of inflammatory cells and osteoclasts. These results suggested that XCL1 might be involved in the development of periprosthetic osteolysis through promoting infiltration of inflammatory cells and bone resorbing-osteoclasts. Our further results demonstrated that supplementing recombinant XCL1 to cultured human monocytes stimulated with the receptor activator of nuclear factor kappa-B ligand (RANKL) promoted osteoclastogenesis and the osteoclast-bone resorbing activity. Moreover, recombinant XCL1 promoted the expression of inflammatory and osteoclastogenic factors, including IL-6, IL-8, and RANKL in human differentiated osteoblasts. Together, these results suggested the potential role of XCL1 in the pathogenesis of periprosthetic osteolysis and aseptic loosening. Our data broaden knowledge of the pathogenesis of aseptic prosthesis loosening and highlight a novel molecular target for therapeutic intervention.

BackgroundArticular surface damage commonly associated with rupture of the anterior cruciate ligament (ACL). Large osteochondral defect, which consists of a severe depression fracture and a large cartilage defect, need to be treated due to deformation of the articular surface as it can impact the clinical outcome of ACL reconstruction. Although autologous chondrocyte implantation is one of the useful options in such cases, it can be questioned whether the reconstruction of the ACL and osteochondral defect should be performed in one procedure alone.Case presentationWe report a case of a 38-year-old male with a deep depression fracture extending to the edge of the lateral femoral condyle associated with ACL injury after twisting his right knee while skiing. The patient was successfully treated with tissue-engineered cartilage transplantation covered by the periosteum with an iliac bone graft combined with anatomic double-bundle ACL reconstruction. Histopathological examination of the transplanted cartilage taken at second-look arthroscopy showed a cartilage-like tissue in the middle to deep zone in which the extracellular matrix was largely stained with Safranin O. The patient was able to return to his previous level of skiing activity without any experience of knee pain. Magnetic resonance imaging at 4 years after surgery showed that the graft integrated to the border zone and subchondral bone. The operated knee showed negative Lachman test and had a full range of motion.ConclusionsTo our knowledge, this is the first report of anatomic double-bundle ACL reconstruction with tissue-engineered cartilage transplantation and an iliac bone graft to restore the lateral edge of the femoral condyle.

Background: During meniscal tissue repair, the origin of the reparative cells of damaged meniscal tissue remains unclear. Hypothesis: Comparison of the influence between meniscal and synovial tissues on meniscal repair by the in vivo freeze-thaw method would clarify the origin of meniscal reparative cells. Study Design: Controlled laboratory study. Methods: A total of 48 mature Japanese white rabbits were divided into 4 groups according to the tissue (meniscal or synovial) that received freeze-thaw treatment. The meniscus of each group had a 2 mm–diameter cylindrical defect filled with alginate gel. Macroscopic and histologic evaluations of the reparative tissues were performed at 1, 3, and 6 weeks postoperatively. Additional postoperative measurements included cell density, which was the number of meniscal cells in the cut area per cut area (mm2) of meniscus; cell density ratio, which was the cell density of the sample from each group per the average cell density of the intact meniscus; and cell death rate, which was the number of cells stained by propidium iodide per the number of cells stained by Hoechst 33342 of the meniscal tissue adjacent to the defect. Results: The macroscopic and histologic evaluations of the non–synovium freeze-thaw groups were significantly superior to those of the synovium freeze-thaw groups at 3 and 6 weeks postoperatively. Additionally, the meniscal cell density ratio and cell death rate in the freeze-thaw groups were significantly lower than those in the non–meniscal freeze-thaw groups at 3 and 6 weeks postoperatively. Conclusion: The freeze-thawed meniscus recovered few cells in its tissue even after 6 weeks. However, the defect was filled with fibrochondrocytes and proteoglycan when the synovium was intact. On the basis of these results, it is concluded that synovial cells are the primary contributors to meniscal injury repair. Clinical Relevance: In meniscal tissue engineering, there is no consensus on the best cell source for meniscal repair. Based on this study, increasing the synovial activity and contribution should be the main objective of meniscal tissue engineering. This study can establish the foundation for future meniscal tissue engineering.

Background:Outcomes and complications at mid- or long-term follow-up after medial open-wedge high tibial osteotomy (MOWHTO) with the TomoFix locking plate have not been fully evaluated.Purpose:To evaluate the complications and midterm clinical outcomes after MOWHTO using a TomoFix.Study Design:Case series; Level of evidence, 4.Methods:Enrolled in this study were 80 patients (85 knees) who underwent MOWHTO with the TomoFix locking plate between 2009 and 2013. There were 66 women and 14 men, with a mean age of 61.5 years at the time of surgery. The diagnosis was medial osteoarthritis in 76 knees and spontaneous osteonecrosis of the knee in 9 knees. Metal removal and second-look arthroscopy were performed in all cases. Clinical and radiological examinations were performed at final follow-up after surgery (mean, 4.5 years).Results:The mean Japanese Orthopaedic Association score and Knee injury and Osteoarthritis Outcome Score improved significantly from pre- to postoperatively ( P < .0001). The weightbearing line percentage shifted to pass through a point 67.7% lateral from the medial edge of the tibial plateau. The Caton-Deschamps index changed significantly from 0.88 to 0.66 at final follow-up ( P < .0001). The mean posterior tibial slope changed significantly from 8.9° to 11.9° at final follow-up ( P < .0001). Limb length was significantly increased after MOWHTO (10.3 mm; P < .0001). During plate removal, 14 locking screws were found to be broken in 9 knees (10.6%). The articular cartilage grade of the patellofemoral joint was significantly higher in the second arthroscopy than in the first arthroscopy ( P < .0001). The cumulative rate of all complications was 41.2%, with major complications (ie, those requiring additional or extended treatment) in 24.7%.Conclusion:Postoperative outcome scores indicated significant improvement after MOWHTO, although the cumulative rate of all complications was 41.2% and the rate of major complications was 24.7%. These results indicate that MOWHTO with the TomoFix is a technically demanding procedure. Careful preoperative planning and meticulous surgical technique are needed to decrease the incidence of complications associated with MOWHTO.

Background: The optimal treatment for a medium- or large-sized cartilage lesion is still controversial. Since an ultrapurified alginate (UPAL) gel enhances cartilage repair in animal models, this material is expected to improve the efficacy of the current treatment strategies for cartilage lesions. Hypothesis: The bone marrow stimulation technique (BMST) augmented by UPAL gel can induce hyaline-like cartilage repair. Study Design: Controlled laboratory study. Methods: Two cylindrical osteochondral defects were created in the patellar groove of 27 beagle dogs. A total of 108 defects were divided into 3 groups: defects without intervention (control group), defects with the BMST (microfracture group), and defects with the BMST augmented by implantation of UPAL gel (combined group). At 27 weeks postoperatively, macroscopic and histological evaluations, micro–computed tomography assessment, and mechanical testing were performed for each reparative tissue. Results: The defects in the combined group were almost fully covered with translucent reparative tissues, which consisted of hyaline-like cartilage with well-organized collagen structures. The macroscopic score was significantly better in the combined group than in the control group ( P < .05). The histological scores in the combined group were significantly better than those in the control group ( P < .01) and microfracture group ( P < .05). Although the repaired subchondral bone volumes were not influenced by UPAL gel augmentation, the mechanical properties of the combined group were significantly better than those of the microfracture group ( P < .05). Conclusion: The BMST augmented by UPAL gel elicited hyaline-like cartilage repair that had characteristics of rich glycosaminoglycan and matrix immunostained by type II collagen antibody in a canine osteochondral defect model. The present results suggest that the current technique has the potential to be one of the autologous matrix-induced chondrogenesis techniques of the future and to expand the operative indications for the BMST without loss of its technical simplicity. Clinical Relevance: The data support the clinical reality of 1-step minimally invasive cartilage-reparative medicine with UPAL gel without harvesting donor cells.

Osteolysis is a serious postoperative complication of total joint arthroplasty that leads to aseptic loosening and surgical revision. Osteolysis is a chronic destructive process that occurs when host macrophages recognize implant particles and release inflammatory mediators that increase bone-resorbing osteoclastic activity and attenuate bone-formation osteoblastic activity. Although much progress has been made in understanding the molecular responses of macrophages to implant particles, the pathways/signals that initiate osteolysis remain poorly characterized. Transcriptomics and gene-expression profiling of these macrophages may unravel key mechanisms in the pathogenesis of osteolysis and aid the identification of molecular candidates for therapeutic intervention. To this end, we analyzed the transcriptional profiling of macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles, the most common components used in bearing materials of orthopedic implants. Regulated genes in stimulated macrophages were involved in cytokine, chemokine, growth factor and receptor activities. Gene enrichment analysis suggested that stimulated macrophages elicited common gene expression signatures for inflammation and rheumatoid arthritis. Among the regulated genes, tumor necrosis factor superfamily member 15 (TNFSF15) and chemokine ligand 20 (CCL20) were further characterized as molecular targets involved in the pathogenesis of osteolysis. Treatment of monocyte cultures with TNFSF15 and CCL20 resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting their potential contribution to loosening between implants and bone tissues. Statement of Significance Implant loosening due to osteolysis is the most common mode of arthroplasty failure and represents a great challenge to orthopedic surgeons and a significant economic burden for patients and healthcare services worldwide. Bone loss secondary to a local inflammatory response initiated by particulate debris from implants is considered the principal feature of the pathogenesis of osteolysis. In the present study, we analyzed the transcriptional profiling of human macrophages exposed to UHMWPE particles and identified a large number of inflammatory genes that were not identified previously in macrophage responses to wear particles. Our data provide a new insight into the molecular pathogenesis of osteolysis and highlights a number of molecular targets with prognostic and therapeutic implications.

In previous studies, numerous approaches were proposed that assess knee cartilage volume quantitatively using 3D magnetic resonance (MR) imaging. However, the clinical use of these approaches is limited because 3D MR is prone to metal artifacts in postoperative cases. Our purpose in this study was to validate a method for knee cartilage volume quantification using conventional MR imaging in patients who underwent anterior cruciate ligament (ACL) reconstruction surgery. The study included 16 patients who underwent MR imaging before and 1 year after ACL reconstruction surgery. Knee cartilage volumes were measured by our computer- based method with the use of T1-weighted sagittal images. We classified the cartilage into eight regions and made comparisons between preoperative and postoperative cartilage volumes in each region. There was a significant difference between preoperative and postoperative cartilage volumes with regard to medial posterior weight-bearing, medial posterior, lateral posterior weight-bearing, and lateral posterior portions (p = 0.006, 0.023, 0.017 and 0.002, respectively). These results were consistent with the previous studies showing that knee cartilage loss occurs frequently in these portions due to an anterior subluxation of the tibia accompanied by ACL tear. With our method, knee cartilage volumes could be measured quantitatively with conventional MR imaging in patients who underwent ACL reconstruction surgery.

We investigated the effect of miR-9 on fibroblast-like synoviocytes (FLS) from RA patients and animal arthritis model. The binding of miR-9 to NF-κB1 3'UTR was analyzed by luciferase reporter assay and immunoprecipitation. ChIP assay and luciferase promoter assay were performed to identify the binding of NF-κB1 to RANKL promoter and its activity. FLS were treated with miR-9/anti-miR-9 to evaluate cell proliferation and the expression of RANKL. Therapeutic effect of intra-articular miR-9 was evaluated in type-II collagen-induced arthritis in rats. miR-9 bound to the 3'-UTR of NF-κB1 and downregulated NF-κB1. NF-κB1 bound to RANKL promoter and increased the promoter activity of RANKL. RANKL was downregulated by miR-9. Proliferation of FLS was increased by miR-9 inhibitor. miR-9 dampened experimental arthritis by lowering inflammatory state, reducing RANKL and osteoclasts formation. Our findings revealed miR-9-NF-κB1-RANKL pathway in RA-FLS, further, miR-9 ameliorated inflammatory arthritis in vivo which propose therapeutic implications of miR- 9 in RA.

BackgroundTo perform medial open-wedge high tibial osteotomy (OWHTO), surgeons expose the medial-proximal tibia by releasing or cutting the superficial layer of the medial collateral ligament (sMCL). Biomechanically, the sMCL provides primary restraint against valgus forces. Therefore, any release of the sMCL can cause valgus instability of the knee joint. The purpose of this study was to assess valgus laxity after release of the medial structure of the knee during OWHTO.MethodsBetween 2009 and 2015, 84 consecutive patients (93 knees) who underwent OWHTO using a locking plate were enrolled in this study. All patients underwent radiological examinations before surgery, during surgery, 1 year after surgery, and after plate removal to objectively assess valgus laxity. The medial joint space (MJS) and the joint line convergence angle (JLCA) of the knee were evaluated using quantitative valgus stress radiography. Clinical evaluation was performed 2 years after surgery.ResultsThe mean functional knee score improved significantly, from 65.5 to 91.1 points (p p ConclusionValgus laxity was significantly greater after release of the sMCL. However, no significant differences were noted in valgus laxity in preoperative, 1-year postoperative periods and after plate removal. Complete release of the sMCL did not cause postoperative valgus laxity after OWHTO surgery.Trial registrationTrial registration number: No.012–0360.

Background A vitamin A derivative, 13-cis-retinoic acid (isotretinoin), has been administered to treat several types of pediatric cancer and has improved survival rates in patients despite being known to induce premature epiphyseal closure. As the number of patients treated by 13-cis-retinoic acid increases, demands for salvage treatment after systemic retinoid therapy are emerging. However, few studies have described the surgical treatment of this disease. Case presentation We report a case with bilateral varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin for neuroblastoma. The patient was successfully treated with correction osteotomy using a Taylor spatial frame in the right knee joint and femoral closed wedge osteotomy using a locking plate in left knee joint. Histopathological examination of the growth plate showed polar irregularity of chondrocytes and decreased cartilage matrix without apoptosis. In contrast, arthroscopic findings showed an intact joint surface. No recurrence of varus deformity was evident on follow-up at 1 year. Conclusions To the best of our knowledge, this represents the first report of correction osteotomy for varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin.

Glycosphingolipids (GSLs) are ubiquitous membrane components that play an indispensable role in maintaining chondrocyte homeostasis. To gain better insight into roles of GSLs, we studied the effects of GSL-deletion on the physiological responses of chondrocytes to mechanical stress. Mice lacking Ugcg gene (Ugcg-/-) were genetically generated to obtain GSL-deficient mice, and their chondrocytes from the joints were used for functional analyses in vitro culture experiments. The cells were seeded in a three-dimensional collagen gel and subjected to 5%, 10% or 16% cyclic tensile strain for either 3 or 24 h. The gene expressions of chondrocyte anabolic and catabolic factors, and the induction of Ca2+ signaling were analyzed. Our results revealed that chondrocytes derived from GSL-deficient mice exhibited an elevation in the expression of catabolic factors (ADAMTS-5, MMP-13) following the exposure to strain with amplitudes of 10%. Likewise, applying cyclic tensile strain with these amplitudes resulted in an increased Ca2+ oscillation ratio in chondrocytes from GSL-deficient as compared to the ratio from control mice. These results demonstrated that deletion of GSL stimulated the catabolic responses of chondrocytes to mechanical stress via the augmentation of the sensitivity to mechanical stress that may lead to the cartilage deterioration. These findings suggest that the regulation of the physiological responses of chondrocytes by GSLs could be a potential target in a therapeutic intervention in osteoarthritis.

OBJECTIVE We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes. METHODS Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity. CONCLUSION These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and indicate a novel therapeutic strategy for RA.

Background This study aimed to clarify the characteristics associated with postoperative floating of the lesser toes, especially focusing on the medial and lateral lessor toes, after arthrodesis of the first metatarsophalangeal joint and resection arthroplasty of the lessor toes in rheumatoid forefoot deformity. Methods Fourty-seven feet of 43 people who underwent resection arthroplasty of the metatarsal head of the lesser toes for rheumatoid arthritis of the metatarsophalangeal joints were included. We retrospectively evaluated the preoperative radiographic findings and clinical characteristics of the patients, and the occurrence of postoperative floating of the lesser toes. The mean duration of follow-up was 36.5 (range 12 to 114) months. Results Preoperative dislocation grades of the second and third toes that demonstrated postoperative floating were significantly higher than those of toes that did not experience postoperative floating. The hallux valgus deformity before surgery was significantly more severe in toes with postoperative floating of the second and third lessor toes than those with no floating (p

Background:Many tissue-engineered methods for meniscal repair have been studied, but their utility remains unclear.Hypothesis:Implantation of low-endotoxin, ultra-purified alginate (UPAL) gel without cells could induce fibrocartilage regeneration on meniscal defects in rabbits.Study Design:Controlled laboratory study.Methods:Forty-two mature Japanese White rabbits were divided into 2 groups of 21 animals each. In each animal, a cylindrical defect measuring 2 mm in diameter was created with a biopsy punch on the anterior horn of the medial meniscus. In the control group, no treatment was applied on the left medial meniscal defect. In the UPAL gel group, the right medial meniscal defect was injected with the UPAL gel and gelated by a CaCl2solution. Samples were evaluated at 3, 6, and 12 weeks postoperatively. For biomechanical evaluation, 6 additional samples from intact animals were used for comparison.Results:The macroscopic score was significantly greater in the UPAL gel group than in the control group at 3 weeks (mean ± SE: 5.6 ± 0.82 vs 3.4 ± 0.83, P = .010), 6 weeks (5.9 ± 0.72 vs 2.5 ± 0.75, P = .026), and 12 weeks (5.2 ± 1.21 vs 1.0 ± 0.63, P = .020). The histological score was significantly greater in the UPAL group than in the control group at 3 weeks (2.1 ± 0.31 vs 1.2 ± 0.25, P = .029) and 12 weeks (2.2 ± 0.55 vs 0.3 ± 0.21, P = .016). The mean stiffness of the reparative tissue in the UPAL gel group was significantly greater than that in the control group at 6 weeks (24.325 ± 3.920 N/mm vs 8.723 ± 1.190 N/mm, P = .006) and at 12 weeks (27.804 ± 6.169 N/mm vs not applicable [because of rupture]).Conclusion:The UPAL gel enhanced the spontaneous repair of fibrocartilage tissues in a cylindrical meniscal defect in rabbits.Clinical Relevance:These results imply that the acellular UPAL gel may improve the repair of traumatic meniscal injuries.

Summary Synovial macrophages that are activated by cartilage fragments initiate synovitis, a condition that promotes hypertrophic changes in chondrocytes leading to cartilage degeneration in OA. In this study, we analyzed the molecular response of chondrocytes under condition of this type of stimulation to identify a molecular therapeutic target. Stimulated macrophages promoted hypertrophic changes in chondrocytes resulting in production of matrix-degrading enzymes of cartilage. Among the top-upregulated genes, FliI was found to be released from activated chondrocytes and exerted autocrine/paracrine effects on chondrocytes leading to an increase in expression of catabolic and hypertrophic factors. Silencing FliI in stimulated cells significantly reduced expression of catabolic and hypertrophic factors in cocultured chondrocytes. Our further results demonstrated that the FliI-TLR4-ERK1/2 axis is involved in the hypertrophic signaling of chondrocytes and catabolism of cartilage. Our findings provide a new insight into the pathogenesis of OA and identify a potentially new molecular target for diagnostics and therapeutics., Graphical abstract, Highlights • Activated macrophages promote the secretion of FliI from chondrocytes • FliI acts as a DAMP-triggering molecule in cartilage • FliI promotes chondrocyte hypertrophy and cartilage catabolism • FliI represents attractive target for therapeutic intervention, Molecular physiology; Immunology; Cell biology

Systemic injection of a nerve growth factor (NGF) antibody has been proven to have a significant relevance in relieving osteoarthritis (OA) pain, while its adverse effects remain a safety concern for patients. A local low-dose injection is thought to minimize adverse effects. In this study, OA was induced in an 8-week-old male Sprague–Dawley (SD) rat joint by monoiodoacetate (MIA) injection for 2 weeks, and the effect of weekly injections of low-dose (1, 10, and 100 µg) NGF antibody or saline (control) was evaluated. Behavioral tests were performed, and at the end of week 6, all rats were sacrificed and their knee joints were collected for macroscopic and histological evaluations. Results showed that 100 µg NGF antibody injection relieved pain in OA rats, as evidenced from improved weight-bearing performance but not allodynia. In contrast, no significant differences were observed in macroscopic and histological scores between rats from different groups, demonstrating that intra-articular treatment does not worsen OA progression. These results suggest that local administration yielded a low effective NGF antibody dose that may serve as an alternative approach to systemic injection for the treatment of patients with OA.

Purpose Eccentric rotational acetabular osteotomy (ERAO) is a modification of rotational acetabular osteotomy (RAO); it has been reported that ERAO allows the femoral head to translate medially and distally. However, no study has compared femoral head translation following RAO or ERAO. The purpose of this study was to compare immediate postoperative translation of the femoral head after RAO and ERAO in comparison with the pre-operative position by radiological methods. Methods Patients treated by RAO or ERAO between 2006 and 2014 were retrospectively evaluated. 19 hips (17 patients) were treated with RAO, and 25 hips (22 patients) were treated with ERAO. The acetabular roof angle and the location of the femoral head were measured on anteroposterior pelvic radiographs. Results The mean pre-operative acetabular roof angle was 20.9° in the RAO group and 22.0° in the ERAO group, showing no significant difference. The mean acetabular roof angle immediately postoperatively was −0.5° in the RAO group and −0.4° in the ERAO group, again showing no significant difference. The mean femoral head translation immediately postoperatively was 3.1 mm (95% confidence interval (CI), 1.5-4.7 mm) laterally and 3.0 mm (95% CI, 1.3-4.7 mm) proximally in the RAO group and 0.8 mm (95% CI, −0.7-2.3 mm) medially and 2.8 mm (95% CI, 1.5-4.1 mm) distally in the ERAO group; this difference was very highly significant (p≤0.001). Conclusions In contrast with RAO, ERAO resulted in significant femoral head translation both medially and distally immediately postoperatively.

Due to the limited intrinsic healing potential of cartilage, injury to this tissue may lead to osteoarthritis. Human induced pluripotent stem cells (iPSCs), which can be differentiated into chondrocytes, are a promising source of cells for cartilage regenerative therapy. Currently, however, the methods for evaluating chondrogenic differentiation of iPSCs are very limited, the main techniques are based on the detection of chondrogenic genes and histological analysis of the extracellular matrix. The cell surface is coated with glycocalyx, a layer of glycoconjugates including glycosphingolipids (GSLs) and glycoproteins. The glycans in glycoconjugates play important roles in biological events, and their expression and structure vary widely depending on cell types and conditions. In this study, we performed a quantitative GSL-glycan analysis of human iPSCs, iPSC-derived mesenchymal stem cell like cells (iPS-MSC like cells), iPS-MSC-derived chondrocytes (iPS-MSC-CDs), bone marrow-derived mesenchymal stem cells (BMSCs), and BMSC-derived chondrocytes (BMSC-CDs) using glycoblotting technology. We found that GSL-glycan profiles differed among cell types, and that the GSL-glycome underwent a characteristic alteration during the process of chondrogenic differentiation. Furthermore, we analyzed the GSL-glycome of normal human cartilage and found that it was quite similar to that of iPS-MSC-CDs. This is the first study to evaluate GSL-glycan structures on human iPS-derived cartilaginous particles under micromass culture conditions and those of normal human cartilage. Our results indicate that GSL-glycome analysis is useful for evaluating target cell differentiation and can thus support safe regenerative medicine.

Vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) is a newly introduced material for prosthetic components that has proven a better mechanical performance with lesser adverse cellular responses than conventional polyethylene in experimental animal models. However, the mechanisms by which VE-UHMWPE particles trigger a reduced osteolytic activity are unclear and remain to be investigated. Therefore, the current study aims at exploring a possible anti-osteolytic mechanism associated with VE-UHMWPE particles. Transcriptional profiling and bioinformatic analyses of human macrophages stimulated by VE-UHMWPE particles revealed a distinct transcriptional program from macrophages stimulated with UHMWPE particles. Out of the up-regulated genes, IL-27 was found to be significantly elevated in macrophages cultured with VE-UHMWPE particles as compared to these with UHMWPE particles (p = 0.0084). Furthermore, we studied the potential anti-osteolytic function of IL-27 in osteolysis murine model. Interestingly, administration of recombinant IL-27 onto calvariae significantly alleviated osteolytic lesions triggered by UHMWPE particles (p = 0.0002). Likewise, IL-27 inhibited differentiation of osteoclasts (p = 0.0116) and reduced inflammatory response (p 0.0001) elicited by conventional UHMWPE particles in vitro. This is the first study demonstrating the involvement of IL-27 in macrophage response to VE-UHMWPE particles and its regulatory role in osteolysis. Our data highlight a novel therapeutic agent for treatment of inflammatory osteolysis induced by polyethylene debris. STATEMENT OF SIGNIFICANCE: Aseptic loosening due to inflammatory osteolysis remains the major cause of arthroplasty failure and represents a substantial economic burden worldwide. Ideal approach to prevent this failure should be directed to minimize inflammatory response triggered by wear particles at the site of implant. Understanding the mechanism by which VE-UHMWPE particles triggers lesser cellular responses and reduced osteolysis as compared to conventional UHMWPE particles may aid in discovery of regulatory factors. In the current study, we reported that IL-27 is a potent regulator of inflammatory osteolysis involved in the reduced biologic activities and osteolytic potentials associated with VE-UHMWPE particles. Initiating the production IL-27 in vivo after total joint arthroplasties might be a novel strategy to prolong the life-spam of implant.

As articular cartilages have rarely healed by themselves because of their characteristics of avascularity and low cell density, surgical intervention is ideal for patients with cartilaginous injuries. Because of structural characteristics of the cartilage tissue, a three-dimensional culture of stem cells in biomaterials is a favorable system on cartilage tissue engineering. Induced pluripotent stem cells (iPSCs) are a new cell source in cartilage tissue engineering for its characteristics of self-renewal capability and pluripotency. However, the optimal cultivation condition for chondrogenesis of iPSCs is still unknown. Here we show that a novel chondrogenic differentiation method of iPSCs using the combination of three-dimensional cultivation in ultra-purified alginate gel (UPAL gel) and multi-step differentiation via mesenchymal stem cell-like cells (iPS-MSCs) could efficiently and specifically differentiate iPSCs into chondrocytes. The iPS-MSCs in UPAL gel culture sequentially enhanced the expression of chondrogenic marker without the upregulation of that of osteogenic and adipogenic marker and histologically showed homogeneous chondrogenic extracellular matrix formation. Our results suggest that the pluripotency of iPSCs can be controlled when iPSCs are differentiated into iPS-MSCs before embedding in UPAL gel. These results lead to the establishment of an efficient three-dimensional system to engineer artificial cartilage tissue from iPSCs for cartilage regeneration. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1086-1093, 2019.

Objective Syndecan 4 has been implicated as a critical mediator of inflammatory responses because of its functions as a coreceptor and reservoir for growth factors and chemokines. Although syndecan 4 is known to be expressed on B cells, its role in immune responses remains unclear. The purpose of this study was to investigate the contribution of syndecan 4 to the development of immune arthritis in murine models. Methods The clinical severity of 3 immunopathologically distinct models, collagen-induced arthritis (CIA), antigen-induced arthritis (AIA), and collagen antibody–induced arthritis (CAIA), was evaluated in wild-type (WT) mice and in syndecan 4–deficient (Sdc4–/–) mice. Germinal center (GC) formation, B cell profiles, humoral immune responses, and B cell migration were analyzed during the course of CIA. Results Sdc4–/– mice were resistant to the induction of CIA, which is T cell and B cell dependent, but AIA and CAIA, which are T cell dependent and T cell independent, respectively, occurred with equal frequency in WT mice and Sdc4–/– mice. Furthermore, Sdc4–/– mice had reduced numbers of B cells and deficient GC formation in draining lymph nodes (DLNs) during the course of CIA, resulting in reduced production of collagen-specific autoantibodies. Compared with B cells from WT mice, B cells from Sdc4–/– mice showed reduced chemotactic migration toward stromal cell–derived factor 1 (SDF-1) and reduced SDF-1–mediated Akt phosphorylation. Consistent with these findings, in vivo transfer experiments showed that fewer Sdc4–/– B cells than WT B cells were found in and around the follicles in the DLNs. Conclusion Our findings suggest that syndecan 4 contributes to the development of CIA by promoting GC formation and autoantibody production through its regulation of SDF-1–mediated B cell migration.

Objective: This study aimed to elucidate the therapeutic effects of intra-articular administration of ultra-purified low endotoxin alginate (UPLE-alginate) on osteoarthritis (OA) using a canine anterior cruciate ligament transection (ACLT) model. Design: We used 20 beagle dogs. ACLT was performed on the left knee of each dog and a sham operation was performed on the right knee as a control. All animals were randomly divided into the control (saline) and therapeutic (UPLE-alginate) groups. Animals in the control and therapeutic groups received weekly injections with 0.7 mL normal saline or 0.7 mL 0.5% UPLE-alginate, respectively, from 0 to 3 weeks after ACLT or sham operation. At 9 weeks after ACLT, the knee joints of all animals were observed using arthroscopy. All animals were euthanized at 14 weeks after ACLT and evaluated using morphologic assessment, histologic assessment, and biomechanical testing. Results: Arthroscopic findings showed intact cartilage surface in both groups. Morphologic findings in the therapeutic group showed milder degeneration compared with those of the control group, but there were no significant differences between groups. Histologic scores of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) were better in the therapeutic group than the control group (MFC: p = 0.009, LFC: p = 0.009). Joint lubrication did not differ significantly between groups. Conclusion: Intra-articular administration of UPLE-alginate in the early stage of OA slowed disease progression in canines. UPLE-alginate may have potential as a therapeutic agent for OA patients and reduce the number of patients who need to undergo total joint arthroplasty. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 3441–3448, 2015.