Hiraku Kikuchi

Factors related to degradation of articular cartilage in osteoarthritis : A review

OBJECTIVES Osteoarthritis (OA) is a common joint deterioration initiated by multiple factors. To better understand related factors in the development of this disease, we focused on the mechanical stress loaded on articular cartilage. MATERIALS AND METHODS The anterior cruciate ligaments of rabbit knee joints were transected, and expression of protein kinase C (PKC) examined immunohistochemically. The PKC activator 12-o-tetradecanoyl-phorbol-13-acetate (TPA) was then administered intraarticularly. To determine the involvement of gas mediators, a cartilage defect was made on the medical femoral condyle of rabbit knee joints. Hydrostatic pressure was loaded on the cartilage taken from the surrounding defects, and levels of superoxide anion and nitric oxide (NO) were measured. Bovine chondrocytes were subjected to cyclic mechanical stretch using a Flexercell Strain Instrument. Proteoglycan synthesis and PKC activity were measured. Expression of matrix metalloproteinase (MMP)-3 and tissue inhibitor of metalloproteinase (TIMP)-1 in articular cartilages obtained from OA patients were examined using Northern blots. RESULTS Chondrocytes from experimentally induced OA were stained positively with anti-alpha-PKC antibody. Intraarticular administration of TPA prevented the development of OA changes. Cyclic tensile stretch loaded on chondrocytes decreased proteoglycan synthesis and PKC activity. Thus, PKC is involved in the stress-mediated degradation of articular cartilage. Cartilage defects led to degradation of surrounding cartilage and to enhanced superoxide anion and NO synthesis. We also noted increased and decreased expressions of MMP-3 and TIMP-1 mRNA in human OA cartilage, respectively. CONCLUSION PKC, gas mediators (superoxide anion, NO), and proteinases are all involved in OA.

Classification of the callus in limb lengthening Radiographic study of 35 limbs

35 calluses formed during limb lengthening were classified radiographically into 6 types: external, straight, attenuated, opposite, pillar, and agenetic. The healing indexes correlated well to the intrinsic periosteal and endosteal conditions of each type. This classification enabled us to estimate the intrinsic conditions, predict the healing index, control the daily lengthening speed, and decide to apply early augmentation of the callus.

Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial

IntroductionWhile many of the commonly used conservative treatments for knee osteoarthritis (OA) have been recognized to be effective, there is still insufficient evidence available. Among the pharmacological treatments for knee OA, oral non-steroidal anti-inflammatory drugs (NSAIDs) act rapidly and are recommended for the management of OA. However, frequent and serious adverse effects of NSAIDs have been recognized. Intra-articular injections of hyaluronic acid (IA-HA) for the treatment of knee OA have been shown to reduce pain and improve joint function. However, there has been no qualified direct comparison study of the efficacy and safety between IA-HA and NSAIDs for patients with knee OA. The aim of this study was to clarify the efficacy and safety of early-phase IA-HA in comparison to those of NSAIDs for patients with knee OA.MethodsThis multicenter, randomized, open-label, parallel-group, non-inferiority comparison study with an oral NSAID involved a total of 200 patients with knee OA. An independent, computer-generated randomization sequence was used to randomly assign patients in a 1:1 ratio to NSAIDs three times per day for five weeks (n = 100) or IA-HA once a week for five weeks (n = 100). The primary endpoint was the percentage change in the patient-oriented outcome measure for knee OA, the Japanese Knee Osteoarthritis Measure (JKOM) score. All patients were questioned regarding any adverse events during treatment. The full analysis set (FAS) was used for analysis. The margin of non-inferiority was 10%.ResultsThe analyses of primary endpoint included 98 patients in the IA-HA group and 86 patients in the NSAID group. The difference in the percentage changes of the JKOM score between the two intervention arms (IA-HA; -34.7% (P<0.001), NSAID; -32.2% (P<0.001)) was -2.5% (95% confidence interval (CI): -14.0 to 9.1), indicating IA-HA was not inferior to NSAID. The frequency of both withdrawal and adverse events in the IA-HA group were significantly lower than those in the NSAID group (P = 0.026 and 0.004, respectively).ConclusionsThe early efficacy of IA-HA is suggested to be not inferior to that of NSAIDs, and that the safety of the early phase of IA-HA is superior to that of NSAIDs for patients with knee OA.Trial registrationUMIN Clinical Trials Registry (UMIN- CTR), UMIN000001026.

P-selectin and platelet-derived microparticles associated with monocyte activation markers in patients with pulmonary embolism.

Platelet activation markers (platelet-derived microparticles and P-selectin on activated platelets), chemokines (monocyte chemotactic peptide and regulated on activation normally T-cell expressed and secreted), and soluble markers (sP-selectin, sE-selectin, sVCAM-1, and sCD14) were measured and compared in patients with pulmonary embolism (PE). These substances are thought to participate in the pathogenesis of PE. Levels of all of the platelet activation markers, chemokines, and soluble markers were higher in the patients with PE than in normal controls. Levels of platelet activation markers were also significantly increased postoperatively after total knee arthroplasty. Anti-platelet therapy significantly inhibited the elevation of platelet activation markers after total knee arthroplasty. These findings suggest that antiplatelet therapy may be useful for PE-related interaction of platelets, leukocytes, and endothelial cells.

A case of malignant transformation in thoracic vertebral hemangioma following repetitive irradiation and extraction

We report a rare case of thoracic vertebral hemangioma which developed into angiosarcoma during the course of repetitive operations and irradiation. A 44 year old female was operated on for hemangioma of the first thoracic vertebra. The diagnosis of hemangioma was confirmed histo‐pathologically with the specimen from the first operation. The tumor developed multiple lesions later in the clinical course after the first operation, these lesions were removed in four consecutive operations and each histologlcai diagnosis was that of hemangioma. Throughout the period of these operations, the patient was treated wtih steroid, and with radiotherapy simultaneously. The patient underwent the fifth operation for the recurrence of the tumor on 26 March 1990, and the histopathological diagnosis was not hemangioma but hemangiosarcoma which was considered a malignant transformation. The tumor cells immunohistochemically revealed positive staining with UEA‐I, Factor‐VIII, as the tumor immunohistochemically showed a vascular endothe‐lioid nature.

SIGNIFICANCE OF SERINE PROTEINASE AND MATRIX METALLOPROTEINASE SYSTEMS IN THE DESTRUCTION OF HUMAN ARTICULAR CARTILAGE

1. During the destruction of articular cartilage, fibrinolytic enzymes and matrix metalloproteinases (MMP) may contribute to the related pathology. The activities, antigens and messenger RNA (mRNA) levels of urokinase‐type plasminogen activator (uPA) and plasminogen activator inhibitor‐1 (PAI‐1) in articular cartilage were measured in patients with no history of joint diseases (control), those with osteoarthritis (OA) classified into osteophyte‐formed site (OS) and weight‐bearing site (WS), and in patients with rheumatoid arthritis (RA).

Effect of urinary trypsin inhibitor on osteoarthritis.

The plasminogen activator (PA) and plasminogen activator inhibitor (PAI) in synovial fluid (SF) of osteoarthritis (OA) were examined to clarify their pathophysiological roles in this disease. Three PAs with molecular weights of 90K, 55K, and 33K were found in the SF, but the 55K PA was dominant. Immunologically, both the 55K and 33K PA were u-PA, while the 90K PA was t-PA. The PAI reacted against both u-PA and t-PA, but the PAI activity against u-PA was much stronger. Urinary trypsin inhibitor (UTI) made a complex with the 55K PA and suppressed the PA activity. A clinical study in which UTI was injected into the joint space of OA (18 joints in 15 patients) revealed excellent (39%), good (16%), and fair (44%) results based on assessment of the pain, range of motion, ballottement and activity of daily living.

Effects of sodium hyaluronic acid on fibrinolytic factors in the synovial fluid (in vivo)

Abstract Twelve patients with osteoarthritis of the knee were administrated hyaluronic acid (HA), and measured for fibrinolytic factors on synovial fluids. It was observed that urokinase-type plasminogen activator (u-PA) activity is enhanced 3 h after administration of HA, and that the activity gradually decreased from the 2nd to the 4th week on the patients whose clinical parameters showed improvement. Antigen of u-PA and PA inhibitor-1 (PAI-1) were increased 3 h after the administration of HA in the cases that improved. However, u-PA antigen gradually decreased from the 2nd to the 4th week similarly to u-PA activity. On the other hand PAI-1 antigen was increased from the 2nd to the 4th week in the improved cases. These results demonstrate that the decrease of fibrinolytic activity in synovial fluid is associated with the improvement of osteoarthritis by treatment with HA.

Effect of cyclic AMP on urokinase-type plasminogen activator receptor and fibrinolytic factors in a human osteoblast-like cell line

We investigated the effect of cyclic AMP (cAMP) on the pericellular fibrinolytic system in NY cells. Dibutyryl cAMP (dbcAMP) or forskolin increased the level of urokinase-type plasminogen activator (u-PA) mRNA and enhanced the secretion of u-PA antigen into the conditioned medium. These agents also increased u-PA antigen on the cell surface. PA inhibitor-1 (PAI-1) antigen was inhibited by dbcAMP or forskolin. Butyrate had no effect on the production and secretion of u-PA and PAI-1. A binding assay of 125I-DFP-u-PA to NY cells revealed a single class of binding sites with a Kd of 3.85 nM and Bmax of 0.89.10(5) binding sites/cell. The Bmax was increased by dbcAMP (1 mM or 10 mM), forskolin (2 microM or 20 microM) of 1.0-, 1.4-, 1.2- and 1.8-fold, respectively. However, the Kd value was not changed. Furthermore, the level of mRNA for the u-PA receptor (u-PAR) was increased by these agents 1.2-, 1.7-, 1.8- and 2.5-fold, respectively. However, butyrate did not alter either the Bmax or the u-PAR mRNA level. These results indicated that the pericellular fibrinolytic activity induced by u-PA/u-PAR is modulated by cAMP in osteoblast-like cells.

Auto-destruction of the articular cartilage and free radical mediators

The effect of static compression on the release of superoxide (SO) and nitric oxide (NO) from cartilage obtained from rabbit knee joints with tissue defects was studied. The rabbits were divided into two groups: (1) those that had 5 mm diameter full chondral defects (defect group) and (2) those in which chondral defects were filled with autogenous perichondrial grafts (grafted group). Histologically, cartilage was regenerated in the grafted group 3 weeks after the operation, although only a fibrous tissue filled the defects in the defect group even 16 weeks after the operation. A static pressure of 5 kg for 10 minutes applied to the cartilage chips obtained from the area surrounding the defects released significant amounts of SO and NO into the medium. Maximum increases were observed in the defect group 3 weeks after the operation.