Relationship of common variants in VEGFA gene with osteonecrosis of the femoral head: A Han Chinese population based association study.

The pathology of non-traumatic osteonecrosis of the femoral head (ONFH) is complex. Several studies have linked some polymorphisms of vascular endothelial growth factors A (VEGFA) with ONFH, but the results are not consistent and are even conflicting. In the study, 22 single nucleotide polymorphisms (SNPs) in VEGFA were genotyped in 1,762 subjects (489 cases and 1,273 controls). Genetic association analyses were performed in single markers and haplotype levels. Stratification analysis was conducted for ONFH patients. Gene by environment interactions were tested between VEGFA and the smoking status of the subjects. Gene expression and eQTL data of significant SNPs were extracted from GTEx to examine their potential biological function. The SNP, rs2010963, was identified to be significantly associated with ONFH (χ2 = 11.66, P = 0.0006, OR = 1.29). Haplotypes including rs2010963 were also identified to be correlated with ONFH in the haplotype-based analyses. After stratifying by the causes of ONFH, a significant signal from rs2010963 could only be identified in alcohol-induced patients (Pallelic = 0.0009) but not in steroid-induced patients (Pallelic = 0.055). No significant results were obtained from the gene by environmental interaction analyses. Significant expression differences of VEGFA were identified in multiple human tissues for different genotypes of rs2010963. Our findings indicate that SNP rs2010963 is significantly associated with ONFH.

[Treatment of multi-segment fracture of complex femoral shaft with instrument-assisted reduction combined with intramedullary interlocking nail fixation].

OBJECTIVE: To investigate the effect of minimally invasive mini-incision and instrumented reduction combined with interlocking intramedullary nailing in the treatment of patients with multi-segment fracture of complex femoral shaft. METHODS: From January 2013 to January 2016, 32 patients with multiple fractures segments of femoral shaft were treated with instrumentation-assisted reduction combined with interlocking intramedullary nailing, including 22 males and 10 females with an average age of 45 years old ranging 17 to 68 years old. The time from injured to operation was 5 to 10 days with an average of 7 days. After admission, routine tibial tubercle or supracondylar bone traction was performed. The patient's general condition was evaluated, the operation time and intraoperative blood loss were recorded. According to Thorsen femoral fracture morphology evaluation criteria and Hohl knee function evaluation of postoperative efficacy, postoperative fracture healing, complications and postoperative recovery of limb function were observed. RESULTS: All patients were followed up for 6 to 24 months with an average of 12 months. The operative time ranged from 48 to 76 minutes with an average of 67 min. The intraoperative blood loss was 150 to 400 ml with an average of 220 ml. The surgical incisions all achieved grade A healing. The fractures reached the clinical standard of healing. The fracture healing time ranged from 4.2 to 10.8 months with an average of 5.7 months. There were no nonunion, incision infection and internal fixation fracture, failure and other complications. According to Thorsen femoral fracture morphology evaluation criteria, the result was excellent in 28 cases, good in 3 cases, fair in 1 case. According to Hohl knee function evaluation criteria, the result was excellent in 30 cases, good in 2 cases. CONCLUSIONS: Instrument-assisted reduction combined with interlocking intramedullary nail fixation is a safe and effective method for the treatment of complex femoral shaft fractures. It has advantages of small trauma, fixed fixation, quick recovery, early postoperative functional exercise.

Genetic association study of common variants in TGFB1 and IL-6 with developmental dysplasia of the hip in Han Chinese population.

Developmental dysplasia of the hip (DDH) is a congenital or developmental deformation or misalignment of the hip joint that is affected by environmental and genetic factors. Recently, polymorphisms in both TGFB1 and IL-6 have been identified as being significantly associated with hip osteoarthritis in Caucasians. In this study, we conducted a case-control study involving 4,206 Han Chinese individuals to investigate the effects of TGFB1 and IL-6 on the disease status and severity of DDH. A total of 32 single-nucleotide polymorphisms (SNPs) were selected to ensure coverage of the two genetic loci. We found SNP rs1800470 in TGFB1 (OR = 1.255, P = 0.0004) and rs1800796 (OR = 0.84, P = 0.0228) in IL-6 to be significantly associated with DDH in this cohort. Further haplotype-based analysis replicated this significant result. Another SNP in IL-6, rs1800796, showed a marginally significant association with DDH. As a non-synonymous SNP, rs1800470 alters the amino acid sequence of the polypeptide encoded by TGFB1; however, bioinformatics analyses revealed that this SNP has limited functional significance. No significant results were obtained in an association study focusing on the severity of DDH and epistasis analysis. Our findings support an important role for TGFB1 in the risk of DDH. Further research is needed to validate the weak association between rs1800796 in IL-6 and DDH.

Polymorphisms of RAD51B are associated with rheumatoid arthritis and erosion in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a common, chronic autoimmune disease affecting 0.5-1.0% of adults worldwide, including approximately 4.5-5.0 million patients in China. The genetic etiology and pathogenesis of RA have not yet been fully elucidated. Recently, one new RA susceptibility gene (RAD51B) has been identified in Korean and European populations. In this study, we designed a two-stage case-control study to further assess the relationship of common variants in the RAD51B gene with increased risk of RA in a total of 965 RA patients and 2,511 unrelated healthy controls of Han Chinese ancestry. We successfully identified a common variant, rs911263, as being significantly associated with the disease status of RA (P = 4.8 × 10-5, OR = 0.64). In addition, this SNP was shown to be related to erosion, a clinical assessment of disease severity in RA (P = 2.89 × 10-5, OR = 0.52). These findings shed light on the role of RAD51B in the onset and severity of RA. More research in the future is needed to clarify the underlying functional link between rs911263 and the disease.

Oxytocin prevents cartilage matrix destruction via regulating matrix metalloproteinases.

Degradation of the extracellular matrix type II Collagen (Col II) induced by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) is an important hallmark of Osteoarthritis (OA). Oxytocin (OT) is a well-known neurohypophysical hormone that is synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus. In this study, we have found that oxytocin receptor (OTR) was expressed in human primary chondrocytes, and the expression of which was reduced in chondrocytes from OA patients and in response to TNF-α treatment in a dose dependent manner. Notably, it was shown that TNF-α -induced degradation of Col II was restored by treatment with OT in a dose-dependent manner. In addition, TNF-α treatment (10 ng/mL) highly elevated the expression of MMP-1 and MMP-13 in SW1353 chondrocytes, which were reversed by OT in a dose dependent manner at both gene and protein expression levels. In addition, it was demonstrated that the JAK2/STAT1 pathway was involved in the restoration effects of OT in the degradation of Col II. Lastly, knockdown of OTR abolished the inhibitory effects of OT on the degradation of col II and the induction of MMP-1 and MMP-13 expression, suggesting the involvement of OTR. Our study implied the therapeutic potential of OT for cartilage degradation.

Protocatechuic acid inhibits osteoclast differentiation and stimulates apoptosis in mature osteoclasts.

BACKGROUND: Imbalance in bone remodeling causes osteoporosis. PURPOSE: In the present study, we identified that protocatechuic acid inhibits osteoclast differentiation and induces apoptosis in RAW264.7 murine macrophage cells. METHODS: Tartrate-resistance acid phosphatase (TRAP) activity was used to determine osteoclast formation. Oxidative stress was analyzed through ROS, lipid peroxide and antioxidant enzyme activities. Osteoclast and inflammatory marker expressions were determined through western blot. Apoptosis induction was determined through membrane potential analysis, Cyt c release and caspase activation. RESULTS: Protocatechuic acid dose dependently reduced RANKL-induced tartrate-resistance acid phosphatase (TRAP) activity and multinucleated osteoclasts formation. Protocatechuic acid inhibited oxidative stress by reducing ROS and lipid peroxide levels with concomitant increase in antioxidant status. Osteoclast specific marker expression (MMP, c-Src, TRAP, TRAF-6, Cathepsin) and transcription factor AP-1 and NFATc1 expression were significantly down regulated by protocatechuic acid. Further, MAPK activation and inflammatory proteins such as NF-kB and COX-2 expressions were significantly down regulated by protocatechuic acid treatment. Further, protocatechuic acid enhanced Nrf-2 translocation into the nucleus. In mature osteoclasts, protocatechuic acid induced apoptosis by inducing mitochondrial membrane potential, cytochrome c release and caspase activation. INTERPRETATION: The present findings shows evidence that, protocatechuic acid prevents osteoclast differentiation through regulating oxidative stress, inflammation and inducing apoptosis in RAW264.7 murine macrophage cells.