Toshihide Shuto

Possible Involvement of the Vascular Endothelial Growth Factor-Flt-1-Focal Adhesion Kinase Pathway in Chemotaxis and the Cell Proliferation of Osteoclast Precursor Cells in Arthritic Joints

Vascular endothelial growth factor (VEGF) plays a crucial role in the pathogenesis of inflammatory joint disease, including angiogenesis and synovitis. Rheumatoid arthritis is a chronic inflammatory disease characterized by progressive synovitis and subsequent bone destruction mediated by osteoclasts (OCs). In this study, we investigate the effects of VEGF on OC precursor cells (pOCs) using Raw cells and adjuvant-induced arthritis in rats. OCs and pOCs in the arthritic joints express VEGF and VEGF receptor type I (Flt-1). Raw cells also express Flt-1, and VEGF treatment stimulated chemotaxis, cell proliferation, the association of Flt-1 with focal adhesion kinase (FAK), and the tyrosine phosphorylation of FAK in Raw cells. The tyrosine phosphorylation of FAK was also observed in pOCs in the arthritic joints of adjuvant-induced arthritis. Adenovirus-mediated expression of FAK-related nonkinase in Raw cells inhibited the effects of VEGF in a dominant negative manner. Furthermore, intra-articular injection of the FAK-related nonkinase virus suppressed the recruitment of pOCs and bone destruction. Our results suggest the possible involvement of the VEGF-Flt-1-FAK pathway in inflammatory disease-induced joint destruction.

Subchondral changes in transient osteoporosis of the hip.

Abstract Objective. To review the subchondral changes on MR imaging in transient osteoporosis of the hip (TOH) and to consider the pathophysiology. Design and patients. MR images of 12 hips of 11 consecutive patients with TOH were retrospectively studied. The diagnoses of TOH were confirmed on the basis of previously published criteria, including decreased bone density of the femoral head and/or neck on radiographs, bone marrow edema (BME) pattern on MR images, spontaneous resolution of the symptoms and a return to normal radiodensity. Results. All 12 hips showed a BME pattern in the femoral head and/or neck. Linear patterns of very low signal intensity were identified on T1-weighted images in the subchondral area within the diffuse low signal intensity area in all 12 hips. On T2-weighted images, a low signal intensity line was observed in the corresponding area in eight hips only. These linear patterns were thought to represent subchondral fracture lines. Conclusions. The presence of a subchondral fracture may be important when considering the pathophysiology of TOH.

Fibroblasts from the inner granulation tissue of the pseudocapsule in hips at revision arthroplasty induce osteoclast differentiation, as do stromal cells

Background: It has previously been shown that many osteoclast precursors are included in the granulation tissue within the pseudocapsule obtained at revision arthroplasty from hips with osteolysis. In vitro culture of only cells isolated from the granulation tissue has been previously shown to generate many mature osteoclasts. Objective: To investigate the presence or otherwise of supporting cells, similar to stromal cells, which differentiate osteoclasts within the granulation tissue. Methods: Cells isolated from the granulation tissue were cultured alone, and after four weeks fibroblast-like cells (granulation fibroblasts) remained. Rat non-adherent bone marrow cells (NA-BMCs) were co-cultured with the granulation fibroblasts with or without 1α,25(OH)2D3 (10−8 M) or heat treated ROS 17/2.8 cell conditioned medium (ht ROSCM), or both. Multinucleated cells (MNCs), which formed, were assessed by biochemical and functional characterisation of osteoclasts. Receptor activator of NFκB ligand (RANKL) was investigated by immunohistochemistry. Results: Co-culture of NA-BMCs and granulation fibroblasts caused the formation of tartrate resistant acid phosphatase (TRAP) positive MNCs, which had the calcitonin receptor (CTR), the Kat-1 antigen, which is specific to the surface of rat osteoclasts, and the ability to form pits in the presence of both 1α,25(OH)2D3 and ht ROSCM or in the presence of just ht ROSCM. RANKL was detected in fibroblast-like cells in the granulation tissue. Conclusion: These data suggest that granulation fibroblasts support osteoclast differentiation, as do osteoblasts/stromal cells, and may play a part in aseptic loosening.

Vertebral strength changes in rheumatoid arthritis patients treated with alendronate, as assessed by finite element analysis of clinical computed tomography scans: A prospective randomized clinical trial†

OBJECTIVE Finite element analysis of clinical computed tomography (CT) scans provides a noninvasive means of assessing vertebral strength that is superior to dual x-ray absorptiometry (DXA)-measured areal bone mineral density. The present study was undertaken to compare strength changes, measured using this newer method, in rheumatoid arthritis (RA) patients who were treated with alendronate (ALN) versus those who were not. METHODS Thirty female RA patients without radiologic signs of L3 compression fractures or a history of osteoporosis medication were enrolled in a prospective randomized clinical trial. Patients were randomly assigned to the ALN group (5 mg orally, once daily) or the control group not receiving antiresorptive treatment. All patients were evaluated by DXA and quantitative CT at baseline and reevaluated after a mean of 12.2 months. Nonlinear finite element analysis was performed on the CT scans (n = 29 available for analysis) to compute an estimate of vertebral compressive strength and to assess strength changes associated with changes in the trabecular compartment and the outer 2 mm of bone (peripheral compartment). RESULTS On average, vertebral strength was significantly decreased from baseline in the control group (n = 15) (median change -10.6%; P = 0.008) but was maintained in the ALN group (n = 14) (median change +0.4%; P = 0.55), with a significant difference between the 2 groups (P < 0.01). Strength decreased more rapidly within the trabecular bone, and ALN treatment was much more effective in the peripheral than the trabecular compartment. CONCLUSION Our results indicate that patients with RA can lose a substantial amount of vertebral strength over a relatively short period of time, and this loss can be prevented by ALN, primarily via its positive effect on the outer 2 mm of vertebral bone.

Aminobisphosphonate (YM175) inhibits bone destruction in rat adjuvant arthritis

Abstract This study was designed to examine the effects of an aminobisphosphonate (YM175, which is also called incadronate) on bone destruction in rat adjuvant arthritis (AA). Thirty-five female Lewis rats were given an intradermal injection of heat-killed Mycobacterium butyricum and randomly allocated to five groups (seven rats/group). In the three YM175-treated (0.01, 0.1 and 1 mg/kg per day) groups, YM175 was injected subcutaneously every day from day 0 to day 42. The effects of YM175 in AA rats were evaluated according to an arthritis score, hind paw volume, and radiological and histological examinations. The results showed that YM175 suppressed the radiological and histopathological changes, as well as the joint swelling, in rat AA in a dose-dependent manner. The number of tartrate-resistant acid phosphatase (TRAP)-positive cells (osteoclasts and preosteoclasts or osteoclast precursors) in bone mar-row spaces and granulation tissue in the YM175-treated groups was also reduced in a dose-dependent manner. This study provides the first evidence that YM175, among aminobisphosphonates, not only inhibits bone destruction in rat AA, probably by reducing osteoclast numbers, but that it also suppresses joint inflammation. These results suggest that YM175 may be a useful drug for the prophylactic treatment of both bone destruction and joint inflammation in patients with rheumatoid arthritis.

Subchondral insufficiency fracture of the femoral head in younger adults

We report two cases of subchondral insufficiency fracture of the femoral head observed in younger adults without any history of overexertion. In both cases, MRI revealed an irregular, discontinuous low-intensity band on the T1-weighted images. Both patients were treated operatively, and histological examination confirmed the diagnosis of subchondral fracture. A diagnosis of subchondral insufficiency fracture needs to be put in as one of the diagnoses in younger patients with a hip pain.

Basic fibroblast growth factor inhibits osteoclast-like cell formation

Basic fibroblast growth factor (bFGF) inhibited osteoclast‐like cell formation in co‐cultures of mouse bone marrow cells either with the mouse stromal cell line, ST2, or with primary osteoblastic cells. Basic FGF significantly inhibited the osteoclast‐like cell formation, induced by 1α,25‐dihydroxyvitamin D3[1α, 25(OH)2D3] when the cytokine was added to the culture, at an intermediate stage, suggesting that bFGF inhibits the differentiation of the osteoclast progenitors. With regard to target cells, bFGF directly affected ST2; it increased [3H]thymidine uptake and decreased the number of alkaline phosphatase‐positive cells. In contrast, bFGF had no inhibitory effect on the colony formation of bone marrow cells induced by macrophage colony stimulating factor in methylcellulose culture. In addition, ST2 cells treated with bFGF produced similar amounts of colony forming activity to those without the cytokine. These findings indicated that the bFGF is not involved in the proliferation of progenitor cells even in the presence of ST2 cells. Furthermore, bFGF inhibited osteoclast‐like cell formation induced not only by 1α,25(OH)2D3, but also by prostaglandin E2 and by interleukin‐11. These results suggest that bFGF inhibits the common site of osteoclast‐like cell formation, as induced by different mechanisms. Our data also indicated that the target cells for bFGF in inhibiting osteoclast formation are not osteoclast progenitors but stromal cells such as ST2 and osteoblastic cells, which support osteoclast development.

Atlantoaxial Instability in Neck Retraction and Protrusion Positions in Patients With Rheumatoid Arthritis

Study Design. Radiographic analysis of the upper cervical spine was performed in patients with rheumatoid arthritis who had C1–C2 instability. Objective. To assess whether neck retraction or neck protrusion movements can cause C1–C2 subluxation in patients with C1–C2 instability. Summary of Background Data. Cervical protrusion is the position where the head is maximally translated anteriorly with zero sagittal rotation, and this position has been shown to produce maximal C1–C2 extension. In contrast, cervical retraction is the position where the head is maximally translated posteriorly, and this position produces maximal C1–C2 flexion. To date, there have been no studies evaluating the effects of these two positions on C1–C2 status in patients with C1–C2 instability. Methods. Twenty-four patients with rheumatoid arthritis who showed an atlantodental interval of at least 5 mm during neck flexion were evaluated in this study. These patients were instructed to actively hold the neck in protrusion and retraction positions, as well as in flexion and extension positions. Lateral cervical radiographs were taken to measure the C1–C2 angle and the atlantodental interval in the sagittal plane in each position. Results. Retraction produced both maximal C1–C2 flexion and anterior C1–C2 subluxation, of a degree just the same as that produced by cervical flexion. Protrusion reversely produced maximal C1–C2 extension. However, 9 of 24 patients exhibited C1–C2 subluxation even in this protrusion position, in marked contrast to the cervical extension position in which only 2 of 24 patients showed C1–C2 subluxation. The patients who showed C1–C2 subluxation in the protrusion position tended to have more severe C1–C2 instability and less capacity for C1–C2 extension than the other patients who achieved a reduction of C1–C2 in the protrusion position. Conclusion. In patients with C1–C2 instability, not only cervical flexion but also cervical retraction constantly led to both maximal C1–C2 flexion and subluxation. In some patients with severe C1–C2 instability, protrusion also resulted in C1–C2 subluxation, even though the C1–C2 was maximally extended.

Transposition osteotomy of the acetabulum for advanced-stage osteoarthritis of the hips

BackgroundTransposition osteotomy of the acetabulum (TOA) was the first periacetabular osteotomy in which the acetabulum was transposed with articular cartilage. TOA improves coverage of the femoral head and joint congruity. The purpose of this study was to investigate whether TOA is an appropriate option for treating osteoarthritis of the hips at the advanced stage by comparing it with matched control hips at the early stage.MethodsBetween 1998 and 2001, TOA was performed in 104 hips of 98 patients. Altogether, 16 of 17 hips (94%) with osteoarthritis at the advanced stage were examined and compared with 37 matched control hips at the early stage. The mean age at the operation was 48 years (38–56 years), and the mean follow-up period was 88 months (65–107 months).ResultsTOA corrected the acetabular dysplasia and significantly improved containment of the femoral head. Clinical scores were also significantly improved in both groups. In the advanced osteoarthritis cases, there was a tendency for abduction congruity before transposition osteotomy of the acetabulum to reflect the clinical outcome.ConclusionsTOA is a promising treatment option for advanced osteoarthritis of the hips as well as for patients at an early stage when preoperative radiographs show good congruity or containment of the joint.

A device for removal of femoral distal cement plug during hip revision arthroplasty: A high-powered drill equipped with a centralizer

A removal procedure of a femoral cement mantle in hip revision arthroplasty has a risk of causing perforation or fracture, especially when removing a well-fixed distal cement plug. A high-powered drill equipped with a centralizer was developed to remove the distal cement plug safely. Using the drill equipped with a centralizer, the cement plug was removed well enough to insert a new component without causing perforation during the operation.