Kensei Nagata

Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis

Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3-signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.

Ghrelin Directly Regulates Bone Formation

To clarify the role of ghrelin in bone metabolism, we examined the effect of ghrelin in vitro and in vivo. Ghrelin and its receptor, GHS‐R1a, were identified in osteoblasts, and ghrelin promoted both proliferation and differentiation. Furthermore, ghrelin increased BMD in rats. Our results show that ghrelin directly affects bone formation.

Interobserver and intraobserver reliability of the japanese orthopaedic association scoring system for evaluation of cervical compression myelopathy.

Study Design. The inter- and intraobserver reliabilities of an assessment scale for cervical compression myelopathy were examined statistically. This scoring system consists of seven categories: motor function of fingers, shoulder and elbow, and lower extremity; sensory function of upper extremity, trunk and lower extremity; and function of the bladder. It evaluates the severity of myelopathy by allocating points based on degree of dysfunction in each category. Objectives. To determine the inter- and intraobserver reliabilities of the revised scoring system (17 − 2 points) for cervical compression myelopathy proposed by the Japanese Orthopedic Association. Summary of Background Data. Several scales to assess clinical outcome from treatment of cervical compression myelopathy have been proposed. Most of these scales include items evaluated by observers. However, no system, including the Japanese Orthopedic Association scoring system, has yet been validated in terms of interobserver reliability. Methods. From five different university hospitals, 10 spine surgery specialists, 10 orthopedic surgeons who had just passed the board examination of the Japanese Orthopedic Association, and 13 residents in the first or second year of orthopedic residency programs were chosen. The participants in this study were 29 patients with myelopathy secondary to ossification of the posterior longitudinal ligament selected from five participating university hospitals. Several surgeons interviewed each patient twice at intervals of 1 to 6 weeks. Inter- and intraobserver reliabilities of the total score for all categories were evaluated by the intraclass correlation coefficient. The extension of the kappa coefficient of Kraemer also was calculated for each category to assess reliability of multivariate categorical data. Results. The interobserver reliability of the total score for the first interview (intraclass correlation coefficient = 0.813) and the intra- and interobserver reliabilities of the total score (intraclass correlation coefficient = 0.826) were high. The level of experience and the hospital slightly affected the reliability of the Japanese Orthopedic Association scoring system. The kappa values for intraobserver data generally were high in each category, whereasthe kappa values for interobserver data were relatively low for the categories of shoulder–elbow motor function and lower extremity sensory function. Conclusions. The inter- and intraobserver reliabilities of the Japanese Orthopedic Association scoring system for cervical myelopathy were high, suggesting that this system is useful for assessment of cervical myelopathy in comparative studies of treatment.

Advanced Glycation End-Products Attenuate Human Mesenchymal Stem Cells and Prevent Cognate Differentiation Into Adipose Tissue, Cartilage, and Bone†‡

The impact of AGEs on human MSCs was studied. AGEs inhibited the proliferation of MSCs, induced apoptosis, and prevented cognate differentiation into adipose tissue, cartilage, and bone, suggesting a deleterious effect of AGEs in the pathogenesis of musculoskeletal disorders in aged and diabetic patients.

Vascular Endothelial Growth Factor in Patients with Rheumatoid Arthritis

To examine the role of vascular endothelial growth factor (VEGF), an endothelial cell specific growth factor, in rheumatoid arthritis (RA), serum concentration of VEGF was examined in patients with RA, osteoarthritis (OA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and control subjects. Serum C-reactive protein (CRP) level, erythrocyte sedimentation rate, white blood cell count and rheumatoid factor titer were also determined in patients with RA. The serum concentration of VEGF was significantly higher in patients with RA than in controls (p < 0.01), and patients with OA (p < 0.05), SLE (p < 0.05), and SS (p < 0.05). The serum concentration of VEGF correlated with serum levels of CRP (r = 0.698, p < 0.0001). The serum concentration of VEGF before treatment was significantly higher than that after treatment in patients with RA who experienced clinical remission (p < 0.05). Our data suggest that VEGF is involved in the pathogenesis of RA and that measurement of serum concentration of VEGF is a noninvasive, useful method for monitoring the disease activity of RA.

Diffusion-weighted imaging of soft tissue tumors: usefulness of the apparent diffusion coefficient for differential diagnosis.

PurposeWe evaluated the efficacy of using the apparent diffusion coefficient (ADC) to differentiate soft tissue tumors.Materials and methodsWe examined 88 histologically proven tumors (44 benign, 8 intermediate, 36 malignant) using diffusion-weighted magnetic resonance images. Images of the tumors were obtained using a single-shot, spin-echo type echo-planar imaging sequence. The tumors were classified histologically as myxoid or nonmyxoid. We then compared the ADC values of the myxoid and nonmyxoid tumors; the benign and malignant myxoid tumors; and the benign, intermediate, and malignant nonmyxoid tumors.ResultsThe mean ADC value of the myxoid tumors (2.08 ± 0.51 × 10−3 mm2/s) was significantly greater than that of the nonmyxoid tumors (1.13 ± 0.40 × 10−3 mm2/s) (P < 0.001). There was no significant difference in the mean ADC values between benign myxoid tumors (2.10 ± 0.50 × 10−3 mm2/s) and malignant myxoid tumors (2.05 ± 0.58 × 10−3 mm2/s). The mean ADC value of benign nonmyxoid tumors (1.31 ± 0.46 × 10−3 mm2/s) was significantly higher than that of malignant nonmyxoid tumors (0.94 ± 0.25 × 10−3 mm2/s) (P < 0.001).ConclusionThe ADC value might be useful for diagnosing the malignancy of nonmyxoid soft tissue tumors.

Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages

Attention has recently focused on the critical role of inflammatory responses in the tumor stroma that provide favorable conditions for cancer‐cell growth and invasion/metastasis. In particular, macrophages recruited into the tumor stroma and activated, known as tumor‐associated macrophages, are suggested to promote tumorigenesis. In this study, we examined the effect of a decrease in the number of monocytes/macrophages in peripheral blood and the tumor stroma on the development of bone and muscle metastases by lung cancer cells. Treatment with clodronate encapsulated by liposomes (Cl2MDP‐LIP) has been developed for the depletion of monocytes/macrophages in an animal model. Subcutaneous administration of Cl2MDP‐LIP markedly reduced the number of monocytes in peripheral blood, resulting in efficient suppression of both bone metastasis and muscle metastasis when lung cancer HARA‐B cells were injected into the left cardiac ventricle of mice. Treatment with Cl2MDP‐LIP significantly reduced the number of macrophages in tumors and the number of osteoclasts in bone marrow, as well as peripheral monocytes in mice harboring lung cancer cells. In contrast, treatment with an osteoclast‐targeting antibiotic, reveromycin A, inhibited bone metastasis by lung cancer cells, but not muscle metastasis. The survival of human macrophages in culture was found to be specifically blocked by Cl2MDP‐LIP, but not by reveromycin A. Cl2MDP‐LIP thus exerted antimetastatic effects in both bone and muscle whereas reveromycin A did so only in bone. Liposome‐encapsulated bisphosphonate may modulate metastasis through decreasing the number of monocytes/macrophages in both peripheral blood and the tumor stroma, suggesting that tumor‐associated macrophages might be suitable targets for antimetastatic therapy. (Cancer Sci 2008; 99: 1595–1602)

Surgical results and related factors for ossification of posterior longitudinal ligament of the thoracic spine: A multi-institutional retrospective study

Study Design. Retrospective multi-institutional study Objective. To describe the surgical outcomes in patients with ossification of the posterior longitudinal ligament in the thoracic spine (T-OPLL) and to clarify factors related to the surgical outcomes. Summary of Background Data. Detailed analyses of surgical outcomes of T-OPLL have been difficult because of the rarity of this disease. Methods. The subjects were 154 patients with T-OPLL who were surgically treated at 34 institutions between 1998 and 2002. The surgical procedures were laminectomy in 36, laminoplasty in 51, anterior decompression via anterior approach in 25 and via posterior approach in 29, combined anterior and posterior fusion in 8, and sternum splitting approach in 5 patients. Instrumentation was conducted in 52 patients. Assessments were made on (1) The Japanese Orthopedic Association (JOA) scores (full score, 11 points), its recovery rates, (2) factors related to surgical results, and (3) complications and their consequences. Results. (1) The mean JOA score before surgery was 4.6 ± 2.0 and, 7.1 ± 2.5 after surgery. The mean recovery rate was 36.8% ± 47.4%. (2) The recovery rate was 50% or higher in 72 patients (46.8%). Factors significantly related to this were location of the maximum ossification (T1–T4) (odds ratio, 2.43–4.17) and the use of instrumentation (odds ratio, 3.37). (3) The frequent complications were deterioration of myelopathy immediately after surgery in 18 (11.7%) and dural injury in 34 (22.1%) patients. Conclusion. The factors significantly associated with favorable surgical results were maximum ossification located at the upper thoracic spine and use of instrumentation. T-OPLL at the nonkyphotic upper thoracic spine can be treated by laminoplasty that is relatively a safe surgical procedure for neural elements. The use of instrumentation allows correction of kyphosis or prevention of progression of kyphosis, thereby, enhancing and maintaining decompression effect, and its use should be considered with posterior decompression.

Reorganization of the primary afferent termination in the rat spinal dorsal horn during post-natal development

To study the reorganization of the primary afferent input in the spinal dorsal horn during post-natal development, synaptic responses evoked by large Abeta and fine Adelta afferents were recorded from substantia gelatinosa (SG) neurons in slices obtained from immature (post-natal days 21-23) and mature rats (post-natal days 56-60). Threshold stimulus intensities and conduction velocities (CVs) of Abeta and Adelta afferents were determined by intracellular recordings of the antidromic action potentials from dorsal root ganglion (DRG) neurons isolated from immature and mature rats. In immature rats, excitatory postsynaptic currents (EPSCs) were elicited by stimulation sufficient to activate Abeta afferents in the majority of SG neurons (64.9%, 24 of 37 neurons), while most EPSCs observed in mature rats were elicited by stimulation of Adelta afferents (62.5%, 25 of 40 neurons). These observations suggest that the primary afferents innervating SG neurons were reorganized following maturation; Abeta afferents were the predominant inputs to the SG neurons in the immature state, thereafter Adelta afferents were substituted for the Abeta afferents to convey sensory information to the SG neurons. This relatively slow reorganization of the sensory circuitry may correlate with slow maturation of the SG neurons and with a delay in the functional connections of C afferents to the SG neurons.

Cervical myelopathy in elderly patients: clinical results and MRI findings before and after decompression surgery

We examined 173 patients with cervical myelopathy of various casuses. Seventy-seven patients underwent anterior decompression and fusion at not more than two levels, while 96 underwent posterior decompression by an expansive laminoplasty. Patients were followed up for between one and 4½ years and the outcome was assessed both from a functional and a radiological point of view. The functional assessment used was according to the Japanese Orthopaedic Association (JOA) score (the higher the better), and the imaging outcome was assessed by a midline sagittal MRI assigned to three categories either for restoration of cord morphology, improvement or unchanged. Patients were divided into two groups: those 65 years old and older (50 patients), and those younger than 65 years old (123 patients). The data allowed the following conclusions to be reached: Older patients were likely to have more levels, and higher levels affected and as a result were more likely to require a posterior operation. The recovery rate after an anterior operation was the same as that after a posterior operation. The pre- and post-operative JOA scores were higher in younger patients who tended to have milder disease with fewer levels affected. Younger patients had better morphological restoration. The recovery was likely to be better if the postoperative morphology was better. The morphology postoperatively was likely to be better if there had been less compression preoperatively. If the morphology was restored the disease duration was likely to have been less. The patients did better if the cord morphology was restored to normal, and this was easier to achieve in younger patients who had fewer levels involved and had less cord distortion preoperatively