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Objectives. Little is known about the biochemical mediators IL-7 that correlate with the initiation and progression of OA. We performed this study to assess the role of variants of IL-7 in OA susceptibility in the Chinese Han population. Methods. We performed a retrospective, case--control study in the Chinese Han population from 2013 to 2015. Four single nucleotide polymorphisms were genotyped (using a ligase detection reaction) in 602 patients and 454 controls. Differences between groups were analysed, and association was assessed by the odds ratio (OR) and 95% CI. Results. Among these polymorphisms, rs2583764, rs2583760 and rs6993386 showed no significant association with OA in the Chinese Han population {rs2583764 [P-allele = 0.98651, P-genotype = 0.40392, OR (95% CI): 1.00162 (0.83066, 1.20775)]; rs2583760 [P-allele = 0.384500, P-genotype = 0.58752, OR (95% CI): 0.69859 (0.30996, 1.57449)]; rs6993386 [P-allele = 0.69525, P-genotype = 0.50712, OR (95% CI): 0.96432 (0.80406, 1.15653)]}. However, the results showed that the rs2583759 polymorphism was significantly associated with OA [P-allele = 0.00 P-genotype = 3.86 x 10-30, OR (95% CI): 0.27794 (0.22407, 0.34476)], even when the 10 000 times permutation was performed (P-allele-permutation < 0.00010, P-genotype-permutation = 0.00010). Haplotype analyses showed A-G-A-C, A-G-A-T and G-G-G-C of rs2583764--rs2583760--rs6993386--rs2583759 were risk factors for OA, both before or after the 10 000 times permutation, indicating IL-7 to be associated with OA. Conclusion. There was a significant association between IL-7, especially rs2583759, and OA in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes (T2D) are both complicated endocrine disorders resulting from an interaction between multiple predisposing genes and environmental triggers, while diet and exercise have key influence on metabolic disorder s. Previous reports demonstrated that 2-aminoadipic acid (2-AAA), an intermediate metabolite of lysine metabolism, could modulate insulin secretion and predict T2D, suggesting the role of 2-AAA in glycolipid metabolism. Here, we showed that treatment of diet-induced obesity (DIO) mice with 2-AAA significantly reduced body weight, decreas ed fat accumulation and lowered fasting glucose. Furthermore, Dhtkd1-/- mice, in which the substrate of DHTKD1 2-AAA increased to a significant high level, were resistant to D IO and obesity-related insulin resistance. Further study showed that 2-AAA induced higher energy expenditure due to increased adipocyte thermogenesis via upregulating PGC1α and UCP1 mediated by β3AR activation, and stimulated lipolysis depending on enhanced expression of hormone-sensitive lipase (HSL) through activating β3AR signaling. Moreover, 2-AAA could alleviate the diabetic symptoms of db/db mice. Our data showed that 2-AAA played an important role in regulating glycolipid metabolism independent of diet and exercise, implying that improving the level of 2-AAA in vivo could be developed as a strategy in the treatment of obesity or diabetes. [ABSTRACT FROM AUTHOR]

DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 that we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive. Here, we show that Dhtkd1-/- mice mimic the major aspects of CMT2 phenotypes, characterized by progressive weakness and atrophy in the distal parts of limbs with motor and sensory dysfunctions, which are accompanied with decreased nerve conduction velocity. Moreover, DHTKD1 deficiency causes severe metabolic abnormalities and dramatically increased levels of 2-ketoadipic acid (2-KAA) and 2-aminoadipic acid (2-AAA) in urine. Further studies revealed that both 2-KAA and 2-AAA could stimulate insulin biosynthesis and secretion. Subsequently, elevated insulin regulates myelin protein zero (Mpz) transcription in Schwann cells via upregulating the expression of early growth response 2 (Egr2), leading to myelin structure damage and axonal degeneration. Finally, 2-AAA-fed mice do reproduce phenotypes similar to CMT2Q phenotypes. In conclusion, we have demonstrated that loss of DHTKD1 causes CMT2Q-like phenotypes through dysregulation of Mpz mRNA and protein zero (Po) which are closely associated with elevated DHTKD1 substrate and insulin levels. These findings further indicate an important role of metabolic disorders in addition to mitochondrial insufficiency in the pathogenesis of peripheral neuropathies. [ABSTRACT FROM AUTHOR]

Evidence indicated that inflammatory response and some pattern-recognition receptors play important roles in the occurrence and progression of osteoarthritis. This study is conducted to evaluate the role of RIG-I and its adaptor protein MAVS in the pathogenesis of osteoarthritis. Four SNPs in RIG-I gene and four in MAVS gene were genotyped in 1056 Chinese Han population. We also overexpressed MAVS in murine chondrogenic ATDC5 cells and analyzed the cell viability and apoptosis. Rs11795343 (P-allele: 0.063394) in RIGI, rs17857295 (P-allele: 0.073518) and rs7262903 (P-allele: 0.054052, P-genotype: 0.067930) in MAVS were marginally associated with OA. Rs7269320 (P-allele: 0.014783, P-genotype: 0.03272) in MAVS was significant associated with OA. Further analyses in different genders indicated that rs7262903 (P-allele: 0.017256, P-genotype: 0.045683) and rs7269320 (P-allele: 0.013073, P-genotype: 0.038881) are significantly associated with OA in female group. Haplotype analyses indicated G-C-G (ρ2: 4.328, P-value: 0.037503) in rs10813821-rs11795343-rs659527 block of RIG-I, G-CA-T (ρ2: 4.056, P-value: 0.044028) and G-C-C-C (ρ2: 14.295, P-value: 0.000158) in rs17857295-rs2326369-rs7262903-rs7269320 block of MAVS were significantly associated with OA. Furthermore, forced expression of MAVS could suppress the viability and promote the apoptosis of ATDC5 chondrogenic cells. In conclusion, this study indicated that RIG-I and MAVS are probably associated with OA in the females of Chinese Han population. And MAVS might be a novel risk factor for OA which may involve in growth of chondrocytes and cartilage homeostasis. [ABSTRACT FROM AUTHOR]

Background: The actin cytoskeleton-associated protein palladin plays an important role in cell motility, morphogenesis and adhesion. In mice, Palladin deficient embryos are lethal before embryonic day (E) 15.5, and exhibit severe cranial neural tube and body wall closure defects. However, the mechanism how palladin regulates the process of cranial neural tube closure (NTC) remains unknown. Methods: In this paper, we use gene knockout mouse to elucidate the function of palladin in the regulation of NTC process. Results: We initially focuse on the expression pattern of palladin and found that in embryonic brain, palladin is predominantly expressed in the neural folds at E9.5. We further check the major cellular events in the neural epithelium that may contribute to NTC during the early embryogenesis. Palladin deficiency leads to a disturbance of cytoskeleton in the neural tube and the cultured neural progenitors. Furthermore, increased cell proliferation, decreased cell differentiation and diminished apical cell apoptosis of neural epithelium are found in palladin deficient embryos. Cell cycle of neural progenitors in Palladin-/- embryos is much shorter than that in wt ones. Cell adhesion shows a reduction in Palladin-/- neural tubes. Conclusions: Palladin is expressed with proper spatio-temporal pattern in the neural folds. It plays a crucial role in regulating mouse cranial NTC by modulating cytoskeleton, proliferation, differentiation, apoptosis, and adhesion of neural epithelium. Our findings facilitate further study of the function of palladin and the underlying molecular mechanism involved in NTC. [ABSTRACT FROM AUTHOR]

Retinoic acid inducible gene I (RIG-I) senses viral RNA5 and triggers innate antiviral responses through induction of type I IFN5 and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κBl. Rig-I is required for NF-κBactivity via regulating F4f-icbl expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-icbl mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-κBl by recruiting the ribosomal proteins [ribosomal protein L13 (Rp113) and Rpl8~ and rRNAS (18S and 285). Down-regulation of Rig-I or Rpll3 significantly reduces Nf-icbl and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-κBsignaling and is involved in multiple biological processes in addition to host antivirus immunity. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors (FGFs) play diverse roles in several developmental processes. Mutations leading to deregulated FGF signaling can cause human skeletal dysplasias and cancer.1,2 Here we report a missense mutation (Ser99Asp) in exon 2 of FGF9 in 12 patients with multiple synostoses syndrome (SYNS) in a large Chinese family. In vitro studies demonstrate that FGF9S99N is expressed and secreted as efficiently as wild-type FGF9 in transfected cells. However, FGF9S99N induces compromised chondrocyte proliferation and differentiation, which is accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells (BMSCs). Biochemical analysis reveals that S99N mutation in FGF9 leads to significantly impaired FGF signaling, as evidenced by diminished activity of Erk1/2 pathway and decreased β-catenin and c-Myc expression when compared with wild-type FGF9. Importantly, the binding of FGF9S99N to its receptor is severely impaired although the dimerization ability of mutant FGF9 itself or with wild-type FGF9 is not detectably affected, providing a basis for the defective FGFR signaling. Collectively, our data demonstrate a previously uncharacterized mutation in FGF9 as one of the causes of SYNS, implicating an important role of FGF9 in normal joint development. [ABSTRACT FROM AUTHOR]