Inhibition of RANKL Expression in Osteocyte-like Differentiated Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment.

Giant cell tumors of bone (GCTBs) are locally aggressive tumors with the histological features of giant cells and stromal cells. Denosumab is a human monoclonal antibody that binds to the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL). RANKL inhibition blocks tumor-induced osteoclastogenesis, and survival, and is used to treat unresectable GCTBs. Denosumab treatment induces osteogenic differentiation of GCTB cells. In this study, the expression of RANKL, special AT-rich sequence-binding protein 2 (SATB2, a marker of osteoblast differentiation), and sclerostin/SOST (a marker of mature osteocytes) was analyzed before and after treatment with denosumab in six cases of GCTB. Denosumab therapy was administered a mean of five times over a mean 93.5-day period. Before denosumab treatment, RANKL expression was observed in one of six cases. After denosumab therapy, spindle-like cells devoid of giant cell aggregation were RANKL-positive in four of six cases. Bone matrix-embedded osteocyte markers were observed, although RANKL was not expressed. Osteocyte-like cells were confirmed to have mutations, as identified using mutation-specific antibodies. Our study results suggest that treatment of GCTBs with denosumab results in osteoblast-osteocyte differentiation. Denosumab played a role in the suppression of tumor activity via inhibition of the RANK-RANKL pathway, which triggers osteoclast precursors to differentiate into osteoclasts.

Identification of anti-citrullinated osteopontin antibodies and increased inflammatory response by enhancement of osteopontin binding to fibroblast-like synoviocytes in rheumatoid arthritis.

BACKGROUND: Anti-citrullinated protein/peptide antibodies (ACPAs) are present in patients at onset and have important pathogenic roles during the course of rheumatoid arthritis (RA). The characteristics of several molecules recognized by ACPA have been studied in RA, but the positivity rate of autoantibodies against each antigen is not high, and the pathogenic mechanism of each antibody is not fully understood. We investigated the role of anti-citrullinated osteopontin (anti-cit-OPN) antibodies in RA pathogenesis. METHODS: Enzyme-linked immunosorbent assays on RA patients' sera were used to detect autoantibodies against OPN. Fibroblast-like synoviocytes (FLS) isolated from RA patients were used to test the binding activity and inflammatory response of OPN mediated by anti-cit-OPN antibodies, and their effect was tested using an inflammatory arthritis mouse model immunized with cit-OPN. Anti-cit-OPN antibody positivity and clinical characteristics were investigated in the patients as well. RESULTS: Using sera from 224 RA patients, anti-cit-OPN antibodies were positive in approximately 44% of RA patients, while approximately 78% of patients were positive for the cyclic citrullinated peptide (CCP2) assay. IgG from patients with anti-cit-OPN antibody increased the binding activity of OPN to FLSs, which further increased matrix metalloproteinase and interleukin-6 production in TNF-stimulated FLSs. Mice immunized with cit-OPN antibodies experienced severe arthritis. Anti-cit-OPN antibodies in RA patients decreased the drug survival rate of tumor necrosis factor (TNF) inhibitors, while it did not decrease that of CTLA4-Ig. CONCLUSIONS: Anti-cit-OPN antibodies were detected in patients with RA. IgG from patients with anti-cit-OPN antibodies aggravated RA, and anti-cit-OPN antibody was a marker of reduced the survival rate of TNF inhibitors in RA patients.

Hip Function Was Not Associated with the Incidence of Preoperative Deep Vein Thrombosis in Patients Undergoing Primary Total Hip Arthroplasty.

The prevalence of preoperative deep vein thrombosis (DVT) has been reported to be relatively high in patients undergoing total hip arthroplasty. We investigated the prevalence of DVT, the association between hip function and preoperative DVT, and the effect of a history of surgery in patients who underwent primary total hip arthroplasty. We retrospectively analyzed the cases of the patients who underwent primary total hip arthroplasty between April 2013 and February 2020 at our institution. We evaluated the prevalence of preoperative DVT based on the results of the patients' ultrasound screening. We performed univariate and multivariate analyses to investigate the association between the incidence of DVT and patient factors including age, sex, hip function, medical histories, and American Society of Anesthesiologists Physical Status classification. We analyzed 451 patients (494 hips). The prevalence of DVT was 14.2% (64 patients). The multivariate analysis demonstrated that increased age was an independent significant risk factor for DVT. The prevalence of preoperative DVT was relatively high among patients who underwent primary total hip arthroplasty. Preoperative DVT tended to be more prevalent in older patients. Hip function was not associated with the incidence of DVT.

Good result for twelve years after bilateral hip and knee arthroplasties for ankylosis with juvenile idiopathic arthritis: a case report.

Juvenile idiopathic arthritis (JIA) can lead to joint deformity and bone destruction, which can cause gait disturbances. To the best of our knowledge, there are no case reports with over 10 years of follow-up on quadruple joint arthroplasties (QJA) for bilateral hip and knee ankylosis associated with JIA. We present the case of a 29-year-old woman with JIA. The patient suffered from bilateral ankylosis of the hips and knees and developed a swing gait requiring double crutches. We performed staged QJA with careful attention to postoperative rehabilitation and her physical features, which included excessive pelvic anteversion, poor bone quality, and short statue of bones. Twelve years after surgery, the patient was able to walk without any support and showed good clinical functional scores. In addition, no radiological loosening following QJA was observed. We hereby introduce a surgical strategy for total hip arthroplasty for excessive pelvic anteversion, which involves two methods to calculate pelvic tilt on a pelvic anteroposterior radiograph. These methods were able to approximately predict postoperative pelvic changes.

Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.

OBJECTIVE: Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine-specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis. METHODS: LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxia-inducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated. RESULTS: In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis. CONCLUSION: LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.

Inverted reamer technique for bone grafting of the acetabulum: technical note.

BACKGROUND: Socket fixation with bone grafting for dysplastic hips is technically demanding, and inadequate coverage of the socket may cause poor results in patients with severely dysplastic hips. An accurate technique to form a bone graft to fit into the defect is necessary. We aim to introduce the simple method of bone grafting, "inverted reamer technique" in cemented total hip arthroplasty (cTHA). METHODS: After acetabular preparation with a normal acetabular reamer, the bone graft was prepared from the resected femoral head with the inverted reamer. The graft can be press-fit into the defect of the acetabulum with good compatibility through this method. Then, the bone graft was fixed with 1-3 screws and the socket was implanted with bone cement. RESULTS: The "inverted reamer technique" can easily and automatically create a well-fit graft. This method is simple and technically less demanding; it can be performed by every surgeon, including trainee and inexperienced surgeons. CONCLUSION: This method can improve the outcome of cTHA for dysplastic hips by preserving bone stock and increasing bone coverage of the socket implanted in the anatomic position.

Unexpected dislocation following accurate total hip arthroplasty caused by excessive hip joint laxity during myasthenic crisis: a case report.

BACKGROUND: Dislocation following total hip arthroplasty is mainly caused by malposition. However, the coexistence of neuromuscular disorders is also considered a risk for dislocation due to excessive hip joint laxity. To minimize risk of dislocation, preoperative planning using combined anteversion has been widely used. The recommended combined anteversion angle (the total of cup and stem anteversion angles) is 50 ± 10°. CASE PRESENTATION: A 33-year-old Japanese woman underwent elective total hip arthroplasty due to osteonecrosis of the femoral head associated with corticosteroid pulse therapy for myasthenia gravis. Intraoperatively, no tendency of dislocation was found when simulating an evoking position under general anesthesia. In postoperative X-ray and computed tomography scans, cup inclination, cup anteversion, and stem anteversion angles were 37°, 13°, and 35° respectively. The resulting combined anteversion was 48°, which was set as the target along with accurate placement. Her postoperative course was normal and she was discharged without adverse events. Three months postoperatively, due to worsening of myasthenic weakness in her lower extremities while resting, she tended to raise her left limb up using both hands for sitting up. An anterior dislocation occurred when her legs were in a figure-of-four position. She was brought to an emergency department, and reduction of dislocation was performed. It was inferred that myasthenic crisis in the affected limb enabled excessive passive motion due to joint hyperlaxity. At the end of 2016, elective total hip arthroplasty on the contralateral side was performed. Cup anteversion, stem anteversion, and the combined anteversion angles were 27°, 24°, and 51° respectively. We instructed her to exercise care during passive leg movement, which may worsen her myasthenic condition. She returned to a normal life and was able to walk long distances without a cane. No recurrence of dislocation was seen at final follow-up. CONCLUSIONS: Even if accurate component orientation is attained in total hip arthroplasty, patients with neuromuscular disorders such as myasthenia gravis have a potential risk of muscle weakness in the affected limb. Therefore, physicians' instructions and patients' careful attention are required to prevent dislocation due to excessive hip joint laxity under conditions of motor weakness.