Hiroomi Tateishi

Association between a Single-Nucleotide Polymorphism in the Promoter of the Human Interleukin-3 Gene and Rheumatoid Arthritis in Japanese Patients, and Maximum-Likelihood Estimation of Combinatorial Effect That Two Genetic Loci Have on Susceptibility to the Disease

Genetic variants of interleukin-3 (IL-3), a well-studied cytokine, may have a role in the pathophysiology of rheumatoid arthritis (RA); but reports on this association sometimes conflict. A case-control study was designed to investigate association between RA and a single-nucleotide polymorphism (SNP) in the IL-3 promoter region. Comparison of cases of RA versus control individuals yielded a chi(2) value of 14.28 (P=.0002), with a genotype odds ratio of 2.24 (95% confidence interval [95%CI] 1.44-3.49). When female cases with earlier onset were compared with female control individuals, the SNP revealed an even more significant correlation, with chi2=21.75 (P=.000004) and a genotype odds ratio of 7.27 (95%CI 2.80-18.89). The stronger association that we observed in this clinically distinct subgroup (females with early onset), within a region where linkage disequilibrium was not significantly extended, suggested that the genuine RA locus should locate either within or close to the IL-3 gene. Combined genotype data on SNPs on eight other candidate genes were combined with our IL-3 results, to estimate relationships between pairs of loci and RA, by maximum-likelihood analysis. The utility of combining the genotype data in this way to identify possible contributions of various genes to this disease is discussed.

Monoclonal expansion of synoviocytes in rheumatoid arthritis

OBJECTIVE To examine whether synoviocytes from patients with rheumatoid arthritis (RA) have a stronger growth ability than those from patients with osteoarthritis (OA), and to determine whether these synoviocytes clonally expand in situ. METHODS Synovial tissues from 13 RA patients and 4 OA patients were cultured, and their ability to form colonies in soft agarose was examined. RA and OA synoviocytes were also examined in varying concentrations of fetal calf serum (FCS)-containing medium to test the effects of FCS on colony formation. DNA was extracted from clones with colony-forming ability in nonpannus lesions and from synoviocytes in pannus lesions. Restriction fragment length polymorphism (RFLP) analysis was used to examine phosphoglycerate kinase 1 (PGK-1) gene patterns. Production of cytokines by these cells was also assessed. RESULTS All 13 RA synoviocytes exhibited colony formation, whereas none of the 4 OA synoviocytes did. This tendency was also seen with all of the concentrations of FCS examined, although growth varied in a dose-dependent manner. In contrast to OA synovial clones, cloned RA synoviocytes obtained from colonies exhibited a partial RFLP PGK-1 gene pattern, suggesting that the clones originated from monoclonal cells. Of note, 3 of 7 noncloned synoviocytes from pannus lesions exhibited a monoclonal pattern. Pannus cells produced high levels of transforming growth factor beta and platelet-derived growth factor. CONCLUSION These findings suggest that synoviocytes with a strong growth ability are present in the rheumatoid synovium, and that these cells expand monoclonally, particularly in pannus lesions.

Relation between interleukin-18 and PGE2 in synovial fluid of osteoarthritis: a potential therapeutic target of cartilage degradation.

Osteoarthritis (OA) is characterized by articular cartilage degradation and hypertrophic joint changes. Interleukin (IL)-18 is a potent inducer of prostaglandin (PG) E2 in vitro. We determined the relation between IL-18 and PGE2 in synovial fluid (SF) of human OA, and discussed the role of IL-18 in the pathogenesis of OA and also its therapeutic consequences. SF was collected from 30 patients with knee OA. The concentrations of IL-18 and other cytokines including IL-1&bgr;, tumor necrosis factor (TNF)-&agr;, IL-6, and IL-8 were measured by enzyme-linked immunosorbent assay (ELISA). The concentration of PGE2 was also assessed by inhibitory ELISA. The average value of IL-18 was 248 ± 310 pg/mL. The average value of PGE2 was 93 ± 103 pg/mL. There was a relatively strong correlation between IL-18 and PGE2 (r = 0.78, p = 0.0001). In contrast, IL-1&bgr; was undetectable (cutoff point of 20 pg/mL), except for one case. TNF-&agr; was also undetectable (cutoff point of 20 pg/mL), except for two cases. The average value of IL-6 was 1,310 ± 2,623 pg/mL (n = 17), whereas IL-8 was 5,208 ± 6,031 pg/mL (n = 5). Furthermore, IL-6 and IL-8 correlated with IL-18 (r = 0.69, p = 0.0024 and r = 0.87, p = 0.0527, respectively). Our results suggest that IL-18 could play a major role in vivo in inducing the production of PGE2, which in turn can cause cartilage degradation in OA pathogenesis. Thus, targeting this cytokine appears to be an important therapeutic approach in OA.

Effect of Posterior Cruciate Sacrifice on the Durability of Total Knee Arthroplasty

We examined the role of the posterior cruciate ligament (PCL) in 202 consecutive PCL-substituting total knee arthroplasties (TKA) performed in 162 patients between November 1984 and December 1995. The average age at surgery was 59.8 years (range 38–85 years). The average follow-up period was 5.4 years (range 2–14 years). The original diagnosis was rheumatoid arthritis in 182 knees and osteoarthritis in 20 knees. All knees were replaced with cemented components. The patients’ knees were evaluated by radiography and by knee kinematics. Using the Knee Society Clinical Rating System, the mean knee score increased from 38.8 to 81.3. at the final follow-up. The incidence of moderate or severe pain was reduced from 85% to 5%. The mean preoperative arc of motion was 98°, and the mean postoperative one was 99°. Overall, 82% of the results were good or excellent at the final follow-up. Complications included posterior dislocation of the prosthesis in 3 knees (1.5%) and postoperative deep infection in 5 knees (2.5%). Tibial radiolucent lines of over 2 mm were observed in 14.5% on the tibial side, and 8.4% on the femoral side at the follow-up. Six prostheses had to be removed: 3 because of persistent instability, and 3 because the tibial component was malpositioned. Compared with the normal control group, neither PCL-substituting TKA nor PCL-retaining TKA showed normal knee kinetics in any case.