Osteogenesis imperfecta (OI) is a heterogenous group of genetic disorders of bone fragility. OI type V is an autosomal-dominant disease characterized by calcification of the forearm interosseous ...membrane, radial head dislocation, a subphyseal metaphyseal radiodense line, and hyperplastic callus formation; the causative mutation involved in this disease has not been discovered yet. Using linkage analysis in a four-generation family and whole-exome sequencing, we identified a heterozygous mutation of c.−14C>T in the 5′-untranslated region of a gene encoding interferon-induced transmembrane protein 5 (IFITM5). It completely cosegregated with the disease in three families and occurred de novo in five simplex individuals. Transfection of wild-type and mutant IFITM5 constructs revealed that the mutation added five amino acids (Met-Ala-Leu-Glu-Pro) to the N terminus of IFITM5. Given that IFITM5 expression and protein localization is restricted to the skeletal tissue and IFITM5 involvement in bone formation, we conclude that this recurrent mutation would have a specific effect on IFITM5 function and thus cause OI type V.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage. We previously reported that C-X-C motif chemokine 10 ...(CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis. However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.
Bone marrow-derived macrophages and CD4
T cells were isolated from wild-type (WT), Cxcl10
, and Cxcr3
mice. CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA. Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice. Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry. Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.
CXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation. Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4
T cells. Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression. In vivo, F4/80
macrophages and CD4
T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10
and Cxcr3
mice. Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.
These findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.
Abstract CXCL10 is a 10 kDa protein, which is categorized functionally as a Th1-chemokine. It binds to the receptor CXCR3 and regulates immune responses through the activation and recruitment of ...leukocytes, such as, T cells, eosinophils, and monocytes. Recent reports have shown that serum and/or tissue expressions of CXCL10 are increased in various autoimmune diseases like rheumatoid arthritis (RA), systemic lupus rythematosus (SLE), Sjogren syndrome (SS), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM). Moreover, CXCL10 and CXCR3 may have important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. Our recent study shows that CXCL10 also has a pathogenic role in bone destruction via receptor activator of NF-κB ligand (RANKL) induction in inflamed synovial tissue of RA. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Further research on the function of this chemokine and interactions between CXCL10 and other cytokines and chemokines may provide therapeutic targets in various autoimmune diseases.
Abstract There are several chemokines and their receptors involved in the pathogenesis of chronic inflammatory arthritis. Of those, CXCL10 and its receptor, CXCR3, are increased in many kinds of ...chronic inflammatory arthritis, especially in rheumatoid arthritis (RA). CXCL10 and CXCR3 play important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Our recent studies show that the crosstalk between CXCL10 and receptor activator of NF-κB ligand (RANKL) in inflamed synovial tissue may induce and perpetuate bone destruction in RA. The interaction between CXCL10 and tumor necrosis factor-α (TNF-α) can also contribute to sustained inflammation in RA. One human trial with anti-CXCL10 monoclonal antibody showed therapeutic potential of blocking CXCL10 in RA treatment. Understanding the novel interaction between this chemokine and other chemokines or cytokines may add possible therapeutic applications in inflammatory arthritis.
Recent MRI studies have demonstrated that the relative orientation of white matter fibers to the B0 field significantly affects R2⁎ measurement. In this work, the origin of this effect was ...investigated by measuring R2 and R2⁎ in multiple orientations and fitting the results to magnetic susceptibility-based models and magic angle-based models. To further explore the source of magnetic susceptibility effect, the contribution of tissue iron to the orientation dependent R2⁎ contrast was investigated. Additionally, the effects of temperature on R2⁎ and orientation dependent R2⁎ contrasts were studied to understand the differences reported between a fixed specimen at room temperature and in vivo at body temperature. The results suggest that the B0 dependent R2⁎ variation is better explained by the magnetic susceptibility-based model with susceptibility anisotropy. However, extracting tissue iron did not reduce the orientation dependent R2⁎ contrast, suggesting iron is not the origin of the contrast. This leaves susceptibility effects from myelin as the most probable origin of the contrast. Temperature showed large contribution on both R2⁎ and orientation dependent R2⁎ contrasts, explaining a portion of the contrast difference between the in-vivo and in-vitro conditions.
We hypothesized that individual differences in intelligence (Spearman's g) are supported by multiple brain regions, and in particular that fluid (gF) and crystallized (gC) components of intelligence ...are related to brain function and structure with a distinct profile of association across brain regions. In 225 healthy young adults scanned with structural and functional magnetic resonance imaging sequences, regions of interest (ROIs) were defined on the basis of a correlation between g and either brain structure or brain function. In these ROIs, gC was more strongly related to structure (cortical thickness) than function, whereas gF was more strongly related to function (blood oxygenation level-dependent signal during reasoning) than structure. We further validated this finding by generating a neurometric prediction model of intelligence quotient (IQ) that explained 50% of variance in IQ in an independent sample. The data compel a nuanced view of the neurobiology of intelligence, providing the most persuasive evidence to date for theories emphasizing multiple distributed brain regions differing in function.
Abstract Nuclear factor E2 p45-related factor 2 (Nrf2) is a transcription factor involved in the expression of cytoprotective genes induced by external stresses. We investigated the role of Nrf2 in ...osteoclast and osteoblast differentiation. Nrf2 knockdown or deletion increased osteoclastic differentiation from bone marrow-derived macrophages (BMMs) through the upregulation of NF-κB, c-Fos, and NFATc1 transcription factors. Nrf2 also inhibited osteoblast differentiation and mineralization via suppression of key regulatory proteins, such as Runx2, osteocalcin, and osterix. Micro-computed tomography and histomorphometric analyses showed an increase in bone mass of Nrf2 knockout compared to that of wild type mice. In addition, the mineral apposition rate and the number of osteoblasts in bone were higher in Nrf2 knockout mice. However, bone resorption parameters, namely DPD and CTX levels, were not affected by Nrf2 deletion. In a coculture condition where calvarial osteoblasts and BMMs from wild type and Nrf2 knockout mice were grown, deletion of Nrf2 in osteoblasts markedly reduced osteoclast formation. This effect was due to an increase in OPG expression in Nrf2 knockout osteoblasts. Taken as a whole, these results indicate that Nrf2 is intrinsically inhibitory to both osteoblast and osteoclast differentiation but its effect on osteoblasts is dominant to its effect on osteoclasts in vivo.
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