Mikihiro Fujioka

A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis

Osteoarthritis (MIM 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Epidemiological and genetic studies have shown that osteoarthritis is a polygenic disease. Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations. A SNP in the 5′ UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 × 10−13) with hip osteoarthritis in two independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (P = 0.0021) and Han Chinese (P = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. Our findings implicate GDF5 as a susceptibility gene for osteoarthritis and suggest that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.

Initial MRI findings of non-traumatic osteonecrosis of the femoral head in renal allograft recipients

Fifty-one renal allograft recipients (15-62 years old, mean: 37 years) were monitored for 2.5-6.5 years (average: 4.3 years) after surgery by using magnetic resonance imaging (MRI) to find (i) initial signs of osteonecrosis of the femoral head (ONF), (ii) the presence of bone marrow edema as an initial sign of ONF, (iii) any changes of MRI patterns, and (iv) the relationship between these MRI findings and prognosis. MRI was performed preoperatively (baseline), and whenever possible during the 6-9th week, 12-16th week, 12th month, and yearly thereafter. T1- and T2-weighted images were obtained by using a spin echo technique. Abnormalities were first detected on MRI of 23 femoral heads in 13 patients between 6 weeks and 12 months. All lesions first showed a low intensity band on T1-weighted images and a high intensity band on T2-weighted images. No symptoms or diffuse patterns, such as bone marrow edema, preceded the appearance of the band pattern. After the 12th month, no new abnormal findings on MRI were detected. The lesions were classified into Type A, B, or C, according to the location. 12 of the 16 Type C femoral head lesions, which extend beyond the medial two thirds of the weight-bearing portion of the acetabulum, became symptomatic 7-14 months after transplantation and then progressed to collapse. Bone marrow edema appeared with radiological collapse and symptoms. With the exception of five lesions in three patients who failed to be MR imaged until 12 months postoperatively, all lesions were first detected on MRI within 16 weeks after transplantation. We therefore postulate that the ischemic event that causes ONF will have occurred within 12 weeks after transplantation, considering the time lag of reparative reaction to the dead bone.

Initial changes of non-traumatic osteonecrosis of femoral head in fat suppression images: bone marrow edema was not found before the appearance of band patterns

The present study examined initial changes in non-traumatic osteonecrosis of the femoral head (ONF) on T1- and T2-weighted MR images, and fat suppression images. The subjects were 57 renal transplant recipients (37 males and 20 females), whose median age at the time of transplantation was 31.5 years old (range, 10 to 58 years). Twelve patients developed band patterns (sign of established ONF) at an early postoperative period. Among them, 4 joints of 3 patients had a localized, faint signal abnormality in fat suppression images, where band pattern was confirmed later in T1- and T2-weighted images. In all the 57 patients, no bone marrow edema preceding to ONF was observed. Bone marrow edema would not be the cause of ONF in renal transplant patients. Early changes depicted in our fat suppression images would be useful information in the studies on pathogenesis of ONF.

Reliability and validity of the Japanese Orthopaedic Association hip score

BackgroundThe Japanese Orthopaedic Association (JOA) hip score has been widely used in Japan as a method to assess hip joint diseases. The JOA hip score consists of four subcategories: pain (Pain), range of motion (ROM), ability to walk (Gait), and activities of daily life (ADL). We present the first report to verify the reliability and validity of the JOA hip score.MethodsA total of 123 patients with osteoarthritis of a unilateral hip and 29 patients with osteonecrosis of a unilateral hip were investigated. The JOA hip score was recorded by orthopedic surgeons in their offices. On the same day, each patient answered a Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) (Japanese version 1.2) by himself or herself. The SF-36 survey measures eight subscales. The internal-consistency reliability of the JOA hip score was evaluated by Cronbach’s coefficient alpha. The validity of the JOA hip score was tested by Spearman’s correlation coefficients between the four subcategories of the JOA hip score and the eight SF-36 subscales.ResultsWhen patients with osteoarthritis with conservative treatment were assessed by the JOA hip score, Cronbach’s coefficient alpha was 0.70, demonstrating internal-consistency reliability. However, when the JOA hip score was used for other groups, Cronbach’s coefficient alpha was <0.70, demonstrating the lack of internal-consistency reliability. Significant correlations were observed between Pain and bodily pain (r = 0.63), between Gait and physical functioning (PF) (r = 0.70), and between ADL and PF (r = 0.81), but not in any other combinations.ConclusionsWe found that the JOA hip score is a reliable system only for patients with osteoarthritis of the hip with conservative treatment. The JOA hip score is a scaling system with convergent and discriminant validity for the assessment of physical function and pain.

Vitamin E prevents steroid-induced osteonecrosis in rabbits.

Background and purpose Prevention of osteonecrosis after corticosteroid administration would be important. We examined the potential of vitamin E (α-tocopherol) to reduce the incidence of corticosteroid-induced osteonecrosis in an animal model. Methods Japanese white rabbits were divided into 2 groups; the control group was fed a normal diet and the experimental group was fed α-tocopherol-supplemented diet in which α-tocopherol (600 mg/kg diet) was added to the normal diet. To induce osteonecrosis, high-dose methylprednisolone acetate (MPSL) (20 mg/kg body weight) was injected once into the right gluteus medius muscle of all rabbits. 4 weeks after the injection of MPSL, the presence or absence of osteonecrosis of bilateral femurs was examined histopathologically. The tocopherol/cholesterol ratios were calculated. The plasma levels of thiobarbituric acid-reactive substances (TBARS) were measured. Results Alpha-tocopherol-supplemented diet reduced the incidence of osteonecrosis, which developed in 14 of 20 rabbits in the control group and 5 of 21 rabbits in the experimental group (p = 0.004). The tocopherol/cholesterol ratio was higher in the experimental group than in the control group after the α-tocopherol administration. The plasma TBARS level was lower in the experimental group than in the control group at 4 weeks after the MPSL administration. Interpretation Our findings may offer a new approach for the prevention of corticosteroid-induced osteonecrosis.BACKGROUND AND PURPOSE Prevention of osteonecrosis after corticosteroid administration would be important. We examined the potential of vitamin E (alpha-tocopherol) to reduce the incidence of corticosteroid-induced osteonecrosis in an animal model. METHODS Japanese white rabbits were divided into 2 groups; the control group was fed a normal diet and the experimental group was fed alpha-tocopherol-supplemented diet in which alpha-tocopherol (600 mg/kg diet) was added to the normal diet. To induce osteonecrosis, high-dose methylprednisolone acetate (MPSL) (20 mg/kg body weight) was injected once into the right gluteus medius muscle of all rabbits. 4 weeks after the injection of MPSL, the presence or absence of osteonecrosis of bilateral femurs was examined histopathologically. The tocopherol/cholesterol ratios were calculated. The plasma levels of thiobarbituric acid-reactive substances (TBARS) were measured. RESULTS Alpha-tocopherol-supplemented diet reduced the incidence of osteonecrosis, which developed in 14 of 20 rabbits in the control group and 5 of 21 rabbits in the experimental group (p = 0.004). The tocopherol/cholesterol ratio was higher in the experimental group than in the control group after the alpha-tocopherol administration. The plasma TBARS level was lower in the experimental group than in the control group at 4 weeks after the MPSL administration. INTERPRETATION Our findings may offer a new approach for the prevention of corticosteroid-induced osteonecrosis.

Relationship between postrenal transplant osteonecrosis of the femoral head and gene polymorphisms related to the coagulation and fibrinolytic systems in Japanese subjects.

Background. Nontraumatic osteonecrosis of the femoral head (ONFH) is one of the complications that may occur after renal transplantation. We investigated the relationship between the incidence of ONFH and polymorphisms in the genes for plasminogen activator inhibitor (PAI)-1, which is one of the major regulatory proteins of the fibrinolytic system, and 5,10-methylenetetrahydrofolate reductase (MTHFR), which is associated with the plasma levels of homocysteine in Japanese subjects. Methods. Thirty-one patients with postrenal transplant ONFH and 106 patients without ONFH were selected. Genotypes of PAI-1 4G/5G and MTHFR C677T were determined by direct sequencing of genomic DNA. In addition, plasma PAI-1 antigen (Ag) levels and plasma total homocysteine (tHcy) levels at the steady state were measured. The relationships between the incidence of ONFH and these genotypes, as well as plasma levels of the gene products, were investigated. Results. Plasma PAI-1 Ag levels were the highest in patients with the 4G/4G genotype, and plasma tHcy levels were the highest in patients with TT genotypes of MTHFR C677T. However, the relationship between the incidence of ONFHH and PAI-1 4G/5G or MTHFR C677T was not observed. The relationship between the incidence of ONFH and plasma levels of PAI-1 Ag or tHcy was not observed. Conclusions. Genotypes of PAI-1 4G/5G and MTHFR C677T or plasma concentrations of PAI-1 Ag and tHcy had no effect on the incidence of ONFH in Japanese subjects, unlike the results of studies performed in white subjects. The effect of genetic background on the pathologic conditions that developed in patients with postrenal transplant ONFH may differ according to race.

Enhanced expression of interleukin-6, matrix metalloproteinase-13, and receptor activator of NF-κB ligand in cells derived from osteoarthritic subchondral bone

BackgroundThe aim of this study was to clarify the significance of subchondral bone in the pathology of osteoarthritis (OA) by investigating the expression of inflammatory cytokines, proteases, and receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK)/osteoprotegerin (OPG) involved in cartilage degeneration.MethodsSubchondral bone was obtained from 19 patients diagnosed with knee OA and 4 patients diagnosed with femoral neck fracture. Subchondral bone osteoblasts (SBOs) were isolated, and total RNA was extracted. Messenger RNA expression of inflammatory cytokines, proteases, and RANKL/RANK/OPG were analyzed using a real-time reverse transcription-polymerase chain reaction (RT-PCR).ResultsReal-time RT-PCR showed that mRNA expressions of interleukin-6 (IL-6), matrix metalloproteinase-13 (MMP-13), and RANKL were significantly enhanced in OA SBOs compared to SBOs without OA. The expressions of these genes was greater in patients with severe cartilage damage than in those with mild cartilage damage. A high correlation between mRNA expression of IL-6 and that of MMP-13 was found in OA SBOs.ConclusionThe increases in IL-6, MMP-13, and RANKL expression in OA SBOs suggest that in subchondral bone OA progression involves abnormal osseous tissue remodeling, which induces mechanical property changes. Cartilage degeneration in OA may also be due, at least in part, to IL-6 and MMP-13 produced by SBOs. Comprehensive research on these pathological features may lead to the development of more effective therapies for OA by administration of molecules that affect bone remodeling and metabolism.

Degree of corticosteroid treatment within the first 2 months of renal transplantation has a strong influence on the incidence of osteonecrosis of the femoral head

Background and purpose  It has been suggested that avascular osteonecrosis (AVN) of the femoral head develops early after renal transplantation. We evaluated the relationship between risk of AVN and dose of steroids administered in different time periods. Methods  Development of AVN was determined using MRI at 3–6 weeks, 9–12 weeks, 24 weeks, and 12 months after transplantation in 150 patients (96 males). We investigated possible associations between acute rejection reactions, the dose of cyclosporine, tacrolimus use, total steroid dose by the second, fourth, sixth, or eighth weeks after transplantation, and incidence of AVN. Results  There was no statistically significant difference between incidence of AVN and presence or absence of an acute rejection reaction. We found a statistically significant association between AVN incidence and the total dose of steroids administered during the first 2 months after transplantation, and there was a doseresponse relationship. No other statistically significant associations were found. Interpretation  Our findings confirm that the total dose of steroids given within the first 2 months after renal transplantation has a great influence on the incidence of AVN.

Short-Term Results of the S-ROM-A Femoral Prosthesis: Operative Strategies for Asian Patients With Osteoarthritis

The S-ROM-A femoral prosthesis (DePuy, Warsaw, IN) is a modular cementless femoral stem system that was developed to adapt to hip joint disorders of Asian patients. Clinical results of total hip arthroplasties using the S-ROM-A femoral prosthesis were evaluated in 68 hips. The average age at the time of surgery was 57.1 years. The mean follow-up period was 27.8 months. The Harris hip score improved from 47.1 points preoperatively to 91.4 points at final follow-up. No dislocations were observed. Implant fixation was good without any evidence of osteolysis or loosening. The S-ROM-A femoral prosthesis fitted well for Asian patients who often have osteoarthritis secondary to developmental dysplasia of the hip, by providing a shorter stem and greater variety in the neck shape of the stem with a smaller diameter.

Effects of alternating current electrical stimulation on lengthening callus.

Limb lengthening by the callotasis method has been clinically applied to patients who suffered from limb length inequality, micromelia, angular deformation and partial bone defect on long bones. However, this technique was time consuming and led to various complications, such as infection at the pin insertion sites, limitation of the range of motion in adjacent joints, muscular weakness and peripheral neuroparalysis. This study was undertaken to investigate whether alternating current electric (AC) stimulation could shorten the maturation period during callotasis. The tibiae of 20 immature male Japanese white rabbits were osteotomized and fixed with external lengthener (Orthofix M100; Orthofix Srl, Bussolengo, Italy). The experimental schedule lasted 5 weeks consisting of 1 week for the latency period, 2 weeks for distraction and 2 weeks for maturation. Twenty rabbits were equally divided into two groups: the control group and the electrical stimulation (ES) group. The control group was not stimulated with an AC stimulator. The ES group was stimulated for 5 weeks just after osteotomy. The obtained results revealed radiologically, electrophysiologically and histologically that AC stimulation accelerated the maturation of lengthened callus and that it could shorten the time course of callus lengthening.