Akihiro Kotani

An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis.

Osteoarthritis is the most common form of human arthritis. We investigated the potential role of asporin, an extracellular matrix component expressed abundantly in the articular cartilage of individuals with osteoarthritis, in the pathogenesis of osteoarthritis. Here we report a significant association between a polymorphism in the aspartic acid (D) repeat of the gene encoding asporin (ASPN) and osteoarthritis. In two independent populations of individuals with knee osteoarthritis, the D14 allele of ASPN is over-represented relative to the common D13 allele, and its frequency increases with disease severity. The D14 allele is also over-represented in individuals with hip osteoarthritis. Asporin suppresses TGF-β–mediated expression of the genes aggrecan (AGC1) and type II collagen (COL2A1) and reduced proteoglycan accumulation in an in vitro model of chondrogenesis. The effect on TGF-β activity is allele-specific, with the D14 allele resulting in greater inhibition than other alleles. In vitro binding assays showed a direct interaction between asporin and TGF-β. Taken together, these findings provide another functional link between extracellular matrix proteins, TGF-β activity and disease, suggesting new therapeutic strategies for osteoarthritis.

Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis

Susceptibility to osteoarthritis, the most common human arthritis, is known to be influenced by genetic factors. Through a genome-wide association study using ∼100,000 SNPs, we have identified a previously unknown gene on chromosome 3p24.3, DVWA, which is associated with susceptibility to knee osteoarthritis. Expressed specifically in cartilage, DVWA encodes a 276-amino-acid protein with two regions corresponding to the von Willebrand factor type A domain (VWA domain). Several DVWA SNPs are significantly associated with knee osteoarthritis in two independent Japanese case-control cohorts. This association was replicated in a Japanese population cohort and a Han Chinese case-control cohort (combined P = 7.3 × 10−11). DVWA protein binds to β-tubulin, and the binding is influenced by two highly associated missense SNPs (rs11718863 and rs7639618) located in the VWA domain. The Tyr169-Cys260 isoform of DVWA, which is overrepresented in knee osteoarthritis, showed weaker interaction. Our findings reveal a new paradigm for study of osteoarthritis etiology and pathogenesis.

A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese

Osteoarthritis (OA) is the most common form of arthritis and is characterized by the gradual loss of articular cartilage. Several OA-susceptibility genes have been identified; however, there are few pharmaceutical targets that can be targeted with small-molecule compounds. To investigate whether a susceptibility gene for OA exists among G-protein-coupled receptors (GPCRs), we performed a stepwise association study for 167 single nucleotide polymorphisms (SNPs) in 44 GPCR genes that were present in cartilage. Through the stepwise association study, an SNP located in the promoter region of EDG2 [endothelial differentiation, lysophosphatidic acid (LPA) GPCR, 2] (-2,820G/A; rs10980705) showed significant association with knee OA in two independent populations (pooled P = 2.6 x 10(-5)). Luciferase and electrophoretic mobility shift assays indicate that this SNP exerts an allelic difference on transcriptional activity and DNA binding in synovial cells, with the susceptibility allele showing increased activity and binding. EDG2 encodes an LPA receptor dominantly expressed in the synovium. The LPA receptor increased the expression of inflammatory cytokines and matrix metalloproteases in synovial cells. Our findings suggest that the LPA-EDG2 signal is involved in the pathogenesis of OA via catabolic process.

Reconstruction of the anterior cruciate ligament using poly-L-lactide interference screws or titanium screws: a comparative study.

In the present clinical trial, interference screws, made of poly-L-lactic acid and applied in 46 knees, were compared to titanium screws employed in 45 knees for reconstructing the anterior cruciate ligament using bone-patellar tendon-bone. An identical surgical technique was applied to both groups; and neither group disclosed apparent side effects such as synovitis caused by hydrolysis of the PLLA or abnormal biochemical findings in the blood. There was no significant difference in the postoperative outcome between the two groups.

Autogenous osteochondral grafts for osteonecrosis of the femoral condyle

Purpose. To evaluate the long-term outcome following use of osteochondral autografts for the treatment of osteonecrosis of the femoral condyle. Methods. Clinical, radiographic and arthroscopic findings were evaluated at follow-up. Patients were 14 women and 2 men, with a mean age of 64.9 years (range, 58–74 years). The osteochondral lesion was equivalent to Lotke 1-B in 12 knees, and was equivalent to 1-C in 4 knees. Preoperative femoral tibia angle ranged from 178° to 190°. Results. The follow-up period ranged from 28 months to 111 months (mean, 67 months). Functional scores improved from 60 to 75 preoperatively to 80 to 100 postoperatively, and the grafts were satisfactorily accepted. Patients with a femoral tibia angle of less than 180° in particular were found to respond favourably. Conclusion. Transplant surgery using osteochondral autografting appeared effective for the treatment of osteonecrosis of femoral condyle.