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 x 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.

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-beta-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-beta 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-beta. Taken together, these findings provide another functional link between extracellular matrix proteins, TGF-beta activity and disease, suggesting new therapeutic strategies for osteoarthritis.

Purpose:Recent studies have shown that low-intensity resistance training with vascular occlusion (kaatsu training) induces muscle hypertrophy. A local hypoxic environment facilitates muscle hypertrophy during kaatsu training. We postulated that muscle hypertrophy can be more efficiently induced by placing the entire body in a hypoxic environment to induce muscle hypoxia followed by resistance training.Methods:Fourteen male university students were randomly assigned to hypoxia (Hyp) and normoxia (Norm) groups (n = 7 per group). Each training session proceeded at an exercise intensity of 70% of 1 repetition maximum (RM), and comprised four sets of 10 repetitions of elbow extension and fexion. Students exercised twice weekly for 6 wk and then muscle hypertrophy was assessed by magnetic resonance imaging and muscle strength was evaluated based on 1RM.Results:Muscle hypertrophy was significantly greater for the Hyp-Ex (exercised fexor of the hypoxia group) than for the Hyp-N (nonexercised fexor of the hypoxia group) or Norm-Ex fexor (P < .05, Bonferroni correction). Muscle hypertrophy was significantly greater for the Hyp-Ex than the Hyp-N extensor. Muscle strength was significantly increased early (by week 3) in the Hyp-Ex, but not in the Norm-Ex group.Conclusion:This study suggests that resistance training under hypoxic conditions improves muscle strength and induces muscle hypertrophy faster than under normoxic conditions, thus representing a promising new training technique.

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10(-13); odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS.

Summary.  Background: Fibrin‐related markers such as soluble fibrin (SF) and D‐dimer are considered useful for the diagnosis of thrombosis. However, the evidence for diagnosis of thrombosis by fibrin‐related markers is not well‐established. Objective: To evaluate the cutoff values of D‐dimer and SF in the diagnosis of thrombosis. Patients and Methods: Plasma concentrations of SF and D‐dimer were measured in 784 inpatients suspected of having thrombosis between 1 August 2003 and 31 December 2004, and then correlated with thrombosis. Results and Conclusions: Plasma concentrations of D‐dimer and SF were significantly higher in patients with disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT) and cerebral thrombosis, compared with those in patients without thrombosis. When cutoff values of > 3.0 μg mL−1 for D‐dimer and > 6.0 μg mL−1 for SF were used for the diagnosis, more than 50% of patients (with the exception of liver transplant patients and postoperative patients) had thrombosis. Receiver operating characteristic analysis showed that SF was more useful than D‐dimer for the diagnosis of thrombosis (i.e. DVT and DIC). The cutoff value of D‐dimer (7.87 μg mL−1) was the same for DVT and DIC, while that of SF was slightly lower for DVT (7.05 μg mL−1) than for DIC (8.60 μg mL−1). Our findings suggest that high levels of plasma fibrin‐related markers reflect high risk for thrombosis.