Masanobu Ohishi

IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages

Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.

SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4. We show here that the suppressor of cytokine-signaling-1 (SOCS1/JAB) is rapidly induced by LPS and negatively regulates LPS signaling. SOCS1(+/-) mice or SOCS1(-/-) mice with interferon-gamma (IFNgamma)-deficient background were more sensitive to LPS-induced lethal effects than were wild-type littermates. LPS-induced NO(2)(-) synthesis and TNFalpha production were augmented in SOCS1(-/-) macrophages. Furthermore, LPS tolerance, a protection mechanism against endotoxin shock, was also strikingly reduced in SOCS1(-/-) cells. LPS-induced I-kappaB and p38 phosphorylation was upregulated in SOCS1(-/-) macrophages, and forced expression of SOCS1 suppressed LPS-induced NF-kappaB activation. Thus, SOCS1 directly suppresses TLR4 signaling and modulates innate immunity.

The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells

OBJECTIVE Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process. METHODS CD4+ T cells, CD14+ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump. RESULTS Tofacitinib treatment of CD4+ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-γ (IFNγ) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14+ monocytes. However, conditioned medium from CD4+ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14+ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage. CONCLUSION Tofacitinib directly suppressed the production of IL-17 and IFNγ and the proliferation of CD4+ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14+ cells and decreased cartilage destruction. In CD4+ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.

Suppressors of Cytokine Signaling-1 and -3 Regulate Osteoclastogenesis in the Presence of Inflammatory Cytokines

Bone metabolism and the immune system have a correlative relationship, and both are controlled by various common cytokines, such as IFNs and ILs, produced in the bone microenvironments. The suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are negative regulators of such cytokines. Although SOCSs are shown to be induced during osteoclast differentiation, their physiological roles in osteoclast differentiation and function have not been clarified. Thus, we examined the roles of SOCS1 and SOCS3 in osteoclastogenesis using SOCS1- and SOCS3-deficient mice. IFN-γ-mediated inhibition of osteoclast differentiation from bone marrow-derived monocytes (BMMs) was strongly enhanced in SOCS1-deficient BMMs, but was diminished in SOCS1-overexpressing BMMs. Moreover, LPS-induced osteoclastogenesis and bone destruction in vivo were suppressed in SOCS1+/− mice compared with those in wild-type mice, suggesting that SOCS1 antagonizes the inhibitory effect of IFN-γ on osteoclastogenesis. SOCS3 did not alter the inhibitory effect of IFNs in osteoclastogenesis in both gain and loss of functional assays; however, the suppressive effect of IL-6 on osteoclast differentiation was greater in SOCS3-deficient BMMs than in wild-type BMMs in vitro. In addition, IL-6 significantly prevented LPS-induced bone destruction in SOCS3-deficient mice, although it failed in wild-type mice in vivo. In SOCS3-deficient BMMs, expression levels of TNF-receptor-associated factor-6 and IκB were drastically reduced and receptor activator of the NF-κB ligand-induced IκB phosphorylation was severely impaired in the presence of IL-6. These data suggest that both SOCS1 and SOCS3 regulate osteoclastogenesis by blocking the inhibitory effect of inflammatory cytokines on receptor activator of the NF-κB ligand-mediated osteoclast differentiation signals. Selective suppression of SOCS1 and SOCS3 in osteoclast precursors may be a possible therapeutic strategy for inflammatory bone destruction.

Wear resistant performance of highly cross-linked and annealed ultra-high molecular weight polyethylene against ceramic heads in total hip arthroplasty

The purpose of this study was to examine the effects of ceramic femoral head material, size, and implantation periods on the wear of annealed, cross‐linked ultra‐high molecular weight polyethylene (UHMWPE) (XLPE) in total hip arthroplasty compared to non‐cross‐linked conventional UHMWPE (CPE). XLPE was fabricated by cross‐linking with 60 kGy irradiation and annealing. Femoral heads made from zirconia and alumina ceramics and cobalt–chrome (CoCr) of 22 or 26 mm diameter were used. In this retrospective cohort study, the femoral head penetration into the cup was measured digitally on radiographs of 367 hips with XLPE and 64 hips with CPE. The average follow‐up periods were 6.3 and 11.9 years, respectively. Both XLPE creep and wear rates were significantly lower than those of CPE (0.19 mm vs. 0.44 mm, 0.0001 mm/year vs. 0.09 mm/year, respectively). Zirconia displayed increased wear rates compared to alumina in CPE; however, there was no difference among head materials in XLPE (0.0008, 0.00007, and −0.009 mm/year for zirconia, alumina, and CoCr, respectively). Neither head size or implantation period impacted XLPE wear. In contrast to CPE, XLPE displayed low wear rates surpassing the effects of varying femoral head material, size, implantation period, and patient demographics. Further follow‐up is required to determine the long‐term clinical performance of the annealed XLPE.

A novel population of cells expressing both hematopoietic and mesenchymal markers is present in the normal adult bone marrow and is augmented in a murine model of marrow fibrosis

Bone marrow (BM) fibrosis is a feature of severe hyperparathyroidism. Consistent with this observation, mice expressing constitutively active parathyroid hormone (PTH)/PTH-related peptide receptors (PPR) in osteoblasts (PPR*Tg) display BM fibrosis. To obtain insight into the nature of BM fibrosis in such a model, a double-mutant mouse expressing constitutively active PPR and green fluorescent protein (GFP) under the control of the type I collagen promoter (PPR*Tg/GFP) was generated. Confocal microscopy and flow cytometry revealed the presence of a cell population expressing GFP (GFP(+)) that was also positive for the hematopoietic marker CD45 in the BM of both PPR*Tg/GFP and control animals. This cell population was expanded in PPR*Tg/GFP. The existence of cells expressing both type I collagen and CD45 in the adult BM was confirmed by IHC and fluorescence-activated cell sorting. An analysis of total RNA extracted from sorted GFP(+)CD45(+) cells showed that these cells produced type I collagen and PTH/PTH-related peptide receptor and receptor activator for NF-κB mRNAs, further supporting their features of being both mesenchymal and hematopoietic lineages. Similar cells, known as fibrocytes, are also present in pathological fibroses. Our findings, thus, indicate that the BM is a permissive microenvironment for the differentiation of fibrocyte-like cells and raise the possibility that these cells could contribute to the pathogenesis of BM fibrosis.

Surgeon Error in Performing Intraoperative Estimation of Stem Anteversion in Cementless Total Hip Arthroplasty

To examine the accuracy of intraoperative estimation of stem anteversion in total hip arthroplasty (THA), we compared the intraoperatively estimated stem anteversion (estimated prosthetic anteversion) to stem anteversion measured by postoperative computed tomography (true anteversion) in 73 hips in 73 patients. Estimated prosthetic anteversion was significantly greater than true anteversion by 5.8°, and the mean absolute value of surgeon error was 7.3° ranging from 11° underestimation to 25° overestimation. Surgeons tended to overestimate when the true anteversion was smaller. A multivariate analysis showed that advanced knee osteoarthritis significantly increased surgeon error. These results indicated that estimated prosthetic anteversion was generally larger than true anteversion and that the grade of knee osteoarthritis affected the degree of surgeon error.

Outcome of joint-preserving arthroplasty for rheumatoid forefoot deformities

Background: Along with the recent advances in the pharmacological management of rheumatoid arthritis, there is a trend toward the use of joint-preserving surgery in the treatment of rheumatoid forefoot deformities. However, the clinical outcomes of joint-preserving surgery for rheumatoid forefoot deformities have not been assessed in comparison to resection arthroplasty. Methods: We retrospectively evaluated 23 feet in 17 patients with rheumatoid forefoot deformities who underwent surgery between January 2010 and December 2013. The patients included 1 male (1 foot) and 16 females (22 feet), with a mean age of 62 years. The mean length of follow-up was 28 months. The patients were treated by 3 surgeons. One surgeon performed joint-preserving procedures (JP group) to the feet in which (1) no pain with motion existed, and (2) the range of motion in the first metatarsophalangeal (MTP) joint was greater than 30 degrees (n = 10); otherwise, resection arthroplasty with arthrodesis of the first MTP joint was performed (n = 3). The other surgeons performed resection arthroplasty in all cases (n = 10) (RA group, n = 13 in total). The clinical outcomes of the patients were evaluated using the Japanese Society for Surgery of the Foot (JSSF) hallux and lesser toe scales. Results: There were no significant differences in the preoperative total JSSF scores for either the hallux (54.5 and 61.4 points) or the lesser toe (45.2 and 57.4 points) between the RA and JP groups, respectively. Postoperatively, the total JSSF scores for both the hallux (79.4 and 88.2 points) and lesser toes (73.6 and 87.7 points) showed significant improvement in both the RA and JP groups, respectively; however, the JP group showed a greater postoperative improvement. The scores relating to the function category on the hallux scale and the alignment category on the lesser toe scale were significantly higher in the JP group. Conclusion: With regard to the function of the hallux and the alignment of the lesser toes, the joint-preserving procedures for rheumatoid forefoot deformities resulted in better clinical outcomes than resection arthroplasty. Level of Evidence: Level III, comparative case series.

Scintigraphic assessments of the reparative process in osteonecrosis of the femoral head using SPECT/CT with 99mTc hydroxymethylene diphosphonate.

ObjectiveThe aim of the study was to assess the degree and location of the reparative process in early osteonecrosis of the femoral head on the basis of single-photon emission computed tomography/computed tomography (SPECT/CT) with technetium-99m hydroxymethylene diphosphonate. Materials and methodsThis study was approved by the institutional review board. We retrospectively evaluated SPECT/CT scans of 23 consecutive hips. On the basis of the classification system used, 12 hips were classified as stage 1 (no radiographic abnormality), six hips as stage 2 (demarcating sclerosis without femoral head collapse), and five hips as stage 3A (<3 mm femoral head collapse). In each femoral head, the area with the maximum uptake count was defined as the region of maximum uptake. The degree of maximum uptake was assessed by the count ratio, which was defined as the maximum count within the femoral head divided by the mean uptake count of the cross-sectional region of the ipsilateral femur at the level of the distal end of the lesser trochanter. ResultsIn stage 1, the maximum uptake count tended to occur in the anterior region of the femoral head. Meanwhile, in both stage 2 and stage 3A, the maximum uptake count was more likely to be observed in the lateral region. The mean count ratio of stage 2 was significantly higher than that of stage 1. ConclusionWe speculate that osteoblastic activity in the precollapsed stage may gradually increase around the necrotic lesion, with a tendency to advance toward the lateral region of the femoral head.

Pelvic tilt and movement during total hip arthroplasty in the lateral decubitus position

Abstract Objectives: Total hip arthroplasty (THA) is often performed in the lateral decubitus (lateral) position. In this position, the pelvis may have various degrees of tilt leading to implant malposition. We sought to quantify the pelvic tilt in lateral position and further pelvic movement during surgery. Methods: In 95 cases with primary THA, three-dimensional pelvic tilts were quantified by superimposing images reconstructed from CT data onto antero-posterior radiographs taken in lateral position at set-up and after cup placement. Pelvises were fixed with a device compressing anterior superior iliac spines and sacrum. Results: Various degrees of pelvic tilt occurred compared to the supine position; sagittal: −3.1° (−25.5° to 10.2°), axial: 3.9° (−8.4° to 17°), coronal: 0.9° (−11.9° to 13.2°). Absolute changes more than 5° were observed 43%, 47%, and 12% in the sagittal, axial, and coronal planes, respectively. The more preoperative posterior pelvic tilt resulted in the more change in the sagittal plane. Further pelvic movement of about 3° in three planes were observed ranging from −11° to 20° after cup placement. Conclusion: This study showed various pelvic tilt and movement during THA. As pelvic tilt directly alters the cup orientation, its changes should be well understood. Improved tools for positioning and holding the pelvis are required.