Tomoko Matsumoto

Insulin-like growth factor-binding proteins (IGFBPs) and their regulatory dynamics.

The IGFBPs are a family of homologous proteins that have co-evolved with the IGFs and that confer upon the IGF regulatory system both functional and tissue specificity. IGFBPs are not merely carrier proteins for IGFs, but hold a central position in IGF ligand-receptor interactions through influences on both the bioavailability and distribution of IGFs in the extracellular environment. In addition, IGFBPs appear to have intrinsic biological activity independent of IGFs. The current status of research on IGFBPs is reviewed herein. Following a brief introduction to the entire IGF/IGFBP system, separate sections for each of the six cloned mammalian IGFBPs, the most extensive for IGFBP3, cover selected topics that emphasize the dynamics of IGFBPs--that is, their regulation in cells, their functionally important post-translational modifications, and their interactions in the cellular microenvironment--and how these dynamics influence physiological function.

Measurement of advanced glycation endproducts in skin of patients with rheumatoid arthritis, osteoarthritis, and dialysis-related spondyloarthropathy using non-invasive methods.

Advanced glycation endproducts (AGEs) are the products of non-enzymatic glycation and oxidation of proteins and lipids. Low-turnover tissues such as articular cartilage seem to be susceptible to the accumulation of AGEs, which might lead to cartilage degradation. Recently, a non-invasive method for measuring skin AGE accumulation was developed by using the Autofluorescence Reader (AFR). To examine the usefulness of measuring skin AGE in patients with bone and joint diseases, we examined autofluorescence (AF) levels in skin of patients with osteoarthritis (OA), rheumatoid arthritis (RA), and dialysis-related spondyloarthropathy (DRSA). Ninety-three patients with RA, 24 patients with OA, and 29 patients with DRSA were examined, and 43 healthy volunteers were used as controls. Skin AF was assessed on the lower arm with the AGE-Reader. Mean AF was significantly higher in the patients with RA (median 2.13 and range 1.25-2.94) or with DRSA (median 2.21 and range 1.29–3.88) than in the patients with OA (median 1.63 and range 1.07–2.31) or in the controls (median 1.74 and range 1.10–2.46). There was no significant difference between OA and the controls, or between RA and DRSA. These findings suggest that differences of AGE accumulation in the skin might reflect the different pathologies of these diseases.

Effects of Insulin-Like Growth Factor I on Transforming Growth Factor β1 Induced Chondrogenesis of Synovium-Derived Mesenchymal Stem Cells Cultured in a Polyglycolic Acid Scaffold

The aim of this study was to demonstrate the induction of chondrogenesis by transforming growth factor (TGF)-β1 from synovium-derived mesenchymal stem cells in a three-dimensional polyglycolic acid (PGA) scaffold, and to evaluate the effects of insulin-like growth factor (IGF)-I on TGF-β1-induced chondrogenesis. Adult human synovial membranes were obtained from the knees of patients with osteoarthritis or rheumatoid arthritis. Cells were expanded in monolayers, seeded onto a PGA scaffold, and cultured for 4 or 8 weeks in chondrogenic medium containing TGF-β1 with or without IGF-I. As a control, the cells were cultured in chondrogenic medium without TGF-β1. The glycosaminoglycan content was quantified using dimethylmethylene blue dye-binding assay, and the DNA content was measured fluorometrically. Histological examination was also performed using safranin-O staining. The expression of mRNA for aggrecan and collagen type II was confirmed by RT-PCR. After 4 weeks of cultivation with TGF-β1, the cells differentiated to a chondrocytic phenotype, and these chondrogeneses were more potent when cultured for 8 weeks. The combination of IGF-I and TGF-β1 produced higher amounts of glycosaminoglycan than TGF-β1 alone at 8 weeks. In conclusions, chondrogenesis from human synovium-derived mesenchymal cells was identified, and IGF-I plays a role in maintaining the extracellular matrix in combination with TGF-β1.

Changes of serum levels of osteocalcin, alkaline phosphatase, IGF-I and IGF-binding protein-3 during fracture healing

The purpose of this study was to determine the changes in serum markers relating to bone formation during fracture healing. Ten consecutive patients with fractures treated with or without surgery were included. Sera were collected periodically from patients for 80-280 (average 180) days after the fracture. The concentrations of intact osteocalcin, bone-specific alkali phosphatase (ALP), insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in the serum were measured by ELISA. All these serum markers increased or decreased after fracture and fluctuated during fracture healing, however, this pattern differed among the cases. In conclusion, serum markers such as osteocalcin, ALP, IGF-I and IGFBP-3 reflected in part the osteoblastic activity during bone formation.

Interleukin-6 levels in synovial fluids of patients with rheumatoid arthritis correlated with the infiltration of inflammatory cells in synovial membrane

To compare the histological appearance of synovial membrane and interleukin (IL)-6 levels in synovial fluids of patients with rheumatoid arthritis (RA). Synovial tissue and synovial fluids were obtained from 51 knee joints with RA undergoing synovectomy or joint replacements. A histological inflammation score was determined based on the hyperplasia of the synovial lining and infiltration of inflammatory cells. The concentrations of IL-6 in synovial fluids were measured by ELISA. The association between IL-6 levels and histological findings was evaluated. We found a positive correlation between the infiltration of inflammation cells in synovial tissues and the concentration of IL-6 in synovial fluids. The IL-6 level in synovial fluid partially reflects histological synovial inflammation.

Gas-sensing characteristics of tin oxide whiskers with different morphologies☆

Abstract Gas-sensing characteristics of three types of tin oxide whiskers with different morphologies were investigated for 2% hydrogen and 2% methane in air as a function of the operating temperature between 300 °C and 700 °C. Whiskers of parallelogrammic cross-section growing in the [010] direction and hexagonal or rhombic cross-sectional whiskers growing in the [110] direction were more sensitive than ribbon-like whiskers growing in the [101] direction with a rectangular cross-section. However, there was no definite correlation between the gas-sensing characteristics and the surface crystallographic structure. In addition, the sensitivity of the whiskers was not dependent upon the whisker thickness. It seemed that the surface roughness was a more important factor in determining the gas sensitivity.

Effect of nonweight bearing on tibial bone density measured by QCT in patients with hip surgery

Abstract: Tibial bone mineral density (BMD) was measured in 11 patients who had undergone hip joint surgery, including 10 women (22–61 years old; mean ± SD = 42.6 ± 10.3) and 1 man (61 years old). Four patients received total hip replacement (THR), while the others underwent rotational acetabular osteotomy (RAO). In one case, the start of rehabilitation was delayed until 4 months after the surgery because of infection at the surgical site. Nine patients underwent hip surgery for osteoarthritis and 2 patients for avascular necrosis. These 2 patients had a history of medication with corticosteroid. BMD of the tibia on the surgically treated side was measured by a peripheral quantitative CT (pQCT) system, which provided three different BMD values of trabecular BMD in the distal portion, total BMD in the distal portion, and total BMD in the diaphysis. The measurements were obtained preoperatively, and at several time points postoperatively, at 2, 4, 6, and 8 weeks and 3, 4, 5, 8, 12, 18, and 24 months after surgery. Brief periods of nonweightbearing lead to significant bone loss, and 1–1.5 years was required to recover to the baseline BMD. Accelerated bone loss was seen in patients in the perimenopausal state, with prolonged bed rest, and in patients receiving corticosteroid. Both trabecular and cortical components were influenced by nonweightbearing and restoration of weightbearing. The decrease in the cortical region occurs after the decrease in the trabecular and endosteal regions.

Growth hormone directly and indirectly stimulates articular chondrocyte cell growth

Although growth hormone (GH) is known to regulate cartilage growth and differentiation during development, it is still unclear whether the cell growth of articular chondrocytes is stimulated directly by GH or mediated by GH-induced insulin-like growth factor-I (IGF-I). In the present study, we focused on whether GH directly or indirectly stimulates articular chondrocyte proliferation. Monolayer articular chondrocytes from 5-week-old male Sprague-Dawley rats were cultured in Hams F-12/Dulbeccos modified essential medium supplemented with 10% fetal bovine serum. Stimulation of DNA synthesis by GH was dose-dependent between 0.1 and 1 microg/ml, and the maximum active concentration of GH was 500 ng/ml, which induced a 3.5-fold increase over control values. Anti-IGF-I antiserum neutralized about 80% of GH-induced DNA synthesis. GH stimulated the secretion of IGF-I into the conditioned medium in a dose-responsive manner. To determine whether GH stimulated DNA synthesis directly, we investigated the time-course changes in mRNA expression of IGF-I and the proto-oncogene c-myc. Induction of IGF-I mRNA occurred at 4 h, and reached a maximum level at 12 h, whereas the expression of c-myc mRNA was induced within 4 h, and continued to increase until 72 h after GH treatment. Furthermore, administration of cycloheximide, an inhibitor of protein synthesis, resulted in the superinduction of both IGF-I and c-myc mRNAs. These results suggest that early induction of c-myc is due to a direct stimulatory effect of GH, and that long-term induction of c-myc was attributable to an indirect effect of GH in which GH-induced secondary proliferative factors may act in an autocrine/paracrine manner. The superinduction of c-myc gene by cycloheximide also indicates that fresh protein synthesis of an intermediate protein was not required for GH-induced c-myc expression. Western ligand blot analysis of IGF-binding proteins revealed that cultured rat articular chondrocytes produced a predominant 41 kDa and a faint 32 kDa form, and that GH significantly stimulated the secretion of the 41 kDa form without affecting expression of the 32 kDa form. Furthermore, a specific IGF-I binding study suggested that the increase in DNA synthesis induced by GH was not associated with changes in affinity or in the number of IGF-I binding sites. These results support the conclusion that the stimulatory effect of GH was mainly mediated by GH-induced IGF-I production in monolayer rat articular chondrocytes. However, it is likely that GH may also have a direct stimulatory effect by inducing c-myc proto-oncogene expression.

A case of pachydermoperiostosis associated with arthritis.

Abstract Pachydermoperiostosis (PDP) is characterized by clubbing fingers, furrowing of the facial skin, and perio-steal hypertrophy. We report a case of a patient with PDP associated with severe arthritis of the knee and ankle joints. His serum C-reactive protein (CRP) levels were increased, and an analysis of serum and synovial fluid showed high levels of interleukin-6. These findings mean that there is some difficulty in distinguishing the disease from rheumatoid arthritis. While treatments such as nonsteroidal anti-inflammatory drugs, steroids, and colchicine were not particularly effective, the severe arthralgia was gradually relieved over a few years.

Bone Mineral Density Is Not Related to Osteophyte Formation in Osteoarthritis of the Hip

Objective. Reports have suggested that bone mineral density (BMD) is higher in patients with osteoarthritis (OA) of the hip than in healthy controls. Various types of OA of the hip caused by osteophyte formation were observed on radiographs during progression to the advanced degenerative stage, and the preoperative type of OA was reported to influence the results of surgical treatment. However, the mechanism underlying the development of different types of OA is still unknown. We measured BMD of patients with hip OA and determined whether higher BMD was observed in patients with osteophyte formation than in those without osteophytes. Methods. We measured BMD of the lumbar spine, radius, and calcaneus using dual-energy x-ray absorptiometry in 88 women who were scheduled to undergo total hip arthroplasty for endstage OA. Hips were evaluated for osteophyte formation using Bombelli’s classification; 31 were graded as atrophic type, 30 as normotrophic, and 27 as hypertrophic. BMD at different skeletal sites were compared among the 3 types of OA. Results. No significant difference in BMD of the lumbar spine, ultradistal radius, mid-radius, or calcaneus was observed among the atrophic, normotrophic, and hypertrophic types of OA. Conclusion. Our data suggest that osteophyte formation is not related to general BMD. Factors other than general bone status, for example the morphology of the hip joint, need to be analyzed to determine the pathomechanism of osteophyte formation in the osteoarthritic hip.