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ObjectiveIt has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA.MethodsThe expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1β stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα.ResultsCD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg).ConclusionsCD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

We investigated the expression and localization of the receptor activator nuclear factor κB ligand (RANKL) in cartilage from patients with rheumatoid arthritis (RA) of relevance to cartilage degeneration. We also examined the role of exogenous lymphotoxin (LT)-α on RANKL expression in human chondrocytes and its effect on in vitro osteoclast differentiation. Cartilage and synovial fluid samples were obtained from 45 patients undergoing total joint replacement surgery or joint puncture, including 24 patients with osteoarthritis (OA) and 21 patients with RA. RANKL expression in articular cartilage was examined by immunohistochemistry. LT-α concentrations in synovial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). Normal human chondrocytes were stimulated with LT-α, and the relative mRNA levels of RANKL, osteoprotegerin (OPG), matrix metalloproteinase-9, and vascular endothelial growth factor were examined by real-time polymerase chain reaction. Soluble RANKL protein in culture media was measured using ELISA, and membrane-bound RANKL protein in cells was examined by western blotting. Co-cultures of human chondrocytes with peripheral blood mononuclear cells (PBMCs) were stimulated with macrophage-colony stimulating factor and LT-α, and osteoclast differentiation was evaluated by staining for tartrate-resistant acid phosphatase. LT-α concentrations were higher in RA synovial fluid than in OA samples. The population of RANKL-positive chondrocytes of RA cartilage was higher than that of OA cartilage, and correlated with cartilage degeneration. Stimulation of cultured human chondrocytes by LT-α increased RANKL expression, the RANKL/OPG ratio, and angiogenic factors. Membrane-bound RANKL in chondrocytes was up-regulated after stimulation of LT-α, whereas soluble RANKL in culture medium did not increase. Co-cultures of human chondrocytes and PBMCs demonstrated that LT-α stimulated human chondrocytes to produce RANKL and induced osteoclastic differentiation of PBMCs. RANKL produced by chondrocytes may contribute to cartilage destruction during RA and LT-α could promote the expression of RANKL in human chondrocytes.

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

/Summary Background Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). Case presentation A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. Conclusions We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations. Key messages Nail-patella syndrome was newly diagnosed on the basis of typical clinical and radiographic findings at the onset of rheumatoid arthritis.

Objective To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. Materials and methods Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain ( COL2A1 ), aggrecan ( ACAN ), ADAMTS4 , ADAMTS5 , MMP13 , and runt-related transcription factor 2 ( RUNX - 2 ) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay. Results COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4 , ADAMTS5 , MMP13, and RUNX2 , and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3. Conclusion Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.

Background To reveal trends in bone microarchitectural parameters with increasing spatial resolution on ultra-high-resolution computed tomography (UHRCT) in vivo and to compare its performance with that of conventional-resolution CT (CRCT) and micro-CT ex vivo . Methods We retrospectively assessed 5 tiger vertebrae ex vivo and 16 human tibiae in vivo . Seven-pattern and four-pattern resolution imaging were performed on tiger vertebra using CRCT, UHRCT, and micro-CT, and on human tibiae using UHRCT. We measured six microarchitectural parameters: volumetric bone mineral density (vBMD), trabecular bone volume fraction (bone volume/total volume, BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), and connectivity density (ConnD). Comparisons between different imaging resolutions were performed using Tukey or Dunnett T3 test. Results The vBMD, BV/TV, Tb.N, and ConnD parameters showed an increasing trend, while Tb.Sp showed a decreasing trend both ex vivo and in vivo . Ex vivo , UHRCT at the two highest resolutions (1024- and 2048-matrix imaging with 0.25-mm slice thickness) and CRCT showed significant differences ( p ≤ 0.047) in vBMD (51.4 mg/cm 3 and 63.5 mg/cm 3 versus 20.8 mg/cm 3 ), BV/TV (26.5% and 29.5% versus 13.8 %), Tb.N (1.3 l/mm and 1.48 l/mm versus 0.47 l/mm), and ConnD (0.52 l/mm 3 and 0.74 l/mm 3 versus 0.02 l/mm 3 , respectively). In vivo , the 512- and 1024-matrix imaging with 0.25-mm slice thickness showed significant differences in Tb.N (0.38 l/mm versus 0.67 l/mm, respectively) and ConnD (0.06 l/mm 3 versus 0.22 l/mm 3 , respectively). Conclusions We observed characteristic trends in microarchitectural parameters and demonstrated the potential utility of applying UHRCT for microarchitectural analysis.

Purpose We report a rare Japanese female who was affected with three genetic-linked diseases: double-level cervical bilateral spondylolysis in association with spina bifida occulta, cleft lip and monostotic fibrous dysplasia of the right proximal femur. The case was considered to be congenital in origin. We also review the pertinent literature of cervical spondylolysis, with a focus on the pathogenesis of multiple-level cervical spondylolysis. Methods A 40-year-old female presented with progressive clumsiness and numbness of the hands. Japanese Orthopedic Association (JOA) score for the cervical spine was 14.5. Plain radiographs of the cervical spine showed bilateral spondylolysis of the articular mass portion, with an adjacent dysplastic change and spina bifida occulta of C4 and C5. Cervical laminoplasty from C4 to C6 was performed. Results The postoperative course was uneventful, and the patient had some recovery of muscle power and sensation, with JOA score improving to 15.5. At the 8-year follow-up, the patient had no recurrence of symptoms, but did show kyphotic and degenerative changes at the C4/5 and C5/6 level with no apparent instability. Conclusions This case is a rare presentation of bilateral cervical spondylolysis involving C4 and C5, presumably congenital, accompanied by combined dysplastic changes of the cervical spine, cleft lip, and fibrous dysplasia, possibly through an error involving an ossification center during the embryonic stage.

We determined mid to long-term results of total elbow arthroplasty (TEA) by use of unlinked elbow prostheses with solid alumina ceramic trochleae, and ceramic ulnar stems (stemmed Kyocera type I; SKC-I) for patients with rheumatoid arthritis. Fifty-four elbows of 39 patients were available for detailed clinical and radiographic review after a follow-up period of at least 5 years. The mean follow-up period was 12.6 years (range 5-22 years). Clinical condition before and after surgery was assessed by use of a modified version of the Mayo Elbow Performance Score (MEPS; 0-100 points) and a Japan Orthopaedic Association Elbow score (JOA score; 0-100 points). The radiographs were reviewed and loosening was defined as a progressive radiolucent line >1 mm wide that was completely circumferential around the prosthesis. Clinical records of post-operative events affecting the elbows were used for survival analysis of the prostheses using the Kaplan-Meier method. The average modified MEPS and JOA scores improved significantly from 39.7 ± 14.3 to 44.7 ± 9.4, respectively, pre-operatively, to 89.7 ± 15.4 and 83.1 ± 12.8, respectively, post-operatively (P< 0.0001). The functional assessment score also improved from 4.9 ± 2.8 to 8.5 ± 3.3 points (P < 0.0001). With loosening or implant revision defined as end points, the likelihood of survival of the prosthesis for up to 20 years was 92.6 % (95 % confidence interval (CI), 85.6-100.0) or 86.3 % (95 % CI 75.0-97.6), respectively. Satisfactory clinical results were obtained after TEA using SKC-I prostheses, which provided excellent pain relief and functional range of motion. The results of our study reveal the high reliability over a long period of the cemented SKC-I prosthesis with an alumina ceramic component.

We investigated the expression and localization of the receptor activator nuclear factor [kappa]B ligand (RANKL) in cartilage from patients with rheumatoid arthritis (RA) of relevance to cartilage degeneration. We also examined the role of exogenous lymphotoxin (LT)-[alpha] on RANKL expression in human chondrocytes and its effect on in vitro osteoclast differentiation. Cartilage and synovial fluid samples were obtained from 45 patients undergoing total joint replacement surgery or joint puncture, including 24 patients with osteoarthritis (OA) and 21 patients with RA. RANKL expression in articular cartilage was examined by immunohistochemistry. LT-[alpha] concentrations in synovial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). Normal human chondrocytes were stimulated with LT-[alpha], and the relative mRNA levels of RANKL, osteoprotegerin (OPG), matrix metalloproteinase-9, and vascular endothelial growth factor were examined by real-time polymerase chain reaction. Soluble RANKL protein in culture media was measured using ELISA, and membrane-bound RANKL protein in cells was examined by western blotting. Co-cultures of human chondrocytes with peripheral blood mononuclear cells (PBMCs) were stimulated with macrophage-colony stimulating factor and LT-[alpha], and osteoclast differentiation was evaluated by staining for tartrate-resistant acid phosphatase. LT-[alpha] concentrations were higher in RA synovial fluid than in OA samples. The population of RANKL-positive chondrocytes of RA cartilage was higher than that of OA cartilage, and correlated with cartilage degeneration. Stimulation of cultured human chondrocytes by LT-[alpha] increased RANKL expression, the RANKL/OPG ratio, and angiogenic factors. Membrane-bound RANKL in chondrocytes was up-regulated after stimulation of LT-[alpha], whereas soluble RANKL in culture medium did not increase. Co-cultures of human chondrocytes and PBMCs demonstrated that LT-[alpha] stimulated human chondrocytes to produce RANKL and induced osteoclastic differentiation of PBMCs. RANKL produced by chondrocytes may contribute to cartilage destruction during RA and LT-[alpha] could promote the expression of RANKL in human chondrocytes.