Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside—a Comprehensive Review

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions

AAV-CRB2 protects against vision loss in an inducible CRB1 retinitis pigmentosa mouse model

Loss of Crumbs homolog 1 (CRB1) or CRB2 proteins in Muller cells or photoreceptors in the mouse retina results in a CRB dose-dependent retinal phenotype. In this study, we present a novel Muller cell-specific Crb1(KO)Crb2(LowMGC) retinitis pigmentosa mouse model (complete loss of CRB1 and reduced levels of CRB2 specifically in Muller cells). The Crb double mutant mice showed deficits in electroretinography, optokinetic head tracking, and retinal morphology. Exposure of retinas to low levels of DL-alpha-aminoadipate acid induced gliosis and retinal disorganization in Crb1(KO)Crb2(LowMGC) retinas but not in wild-type or Crb1-deficient retinas. Crb1(KO)Crb2(LowMGC) mice showed a substantial decrease in inner/outer photoreceptor segment length and optokinetic head-tracking response. Intravitreal application of rAAV vectors expressing human CRB2 (hCRB2) in Muller cells of Crb1(KO)Crb2(LowMGC) mice subsequently exposed to low levels of DL-alpha-aminoadipate acid prevented loss of vision, whereas recombinant adeno-associated viral (rAAV) vectors expressing human CRB1 (hCRB1) did not. Both rAAV vectors partially protected the morphology of the retina. The results suggest that hCRB expression in Muller cells is vital for control of retinal cell adhesion at the outer limiting membrane, and that the rAAV-cytomegalovirus (CMV)-hCRB2 vector is more potent than rAAV-minimal CMV (CMVmin)-hCRB1 in protection against loss of vision.Ophthalmic researc

A Note on Energy-Momentum Conservation in Palatini Formulation of L(R) Gravity

By establishing that Palatini formulation of $L(R)$ gravity is equivalent to $\omega=-3/2$ Brans-Dicke theory, we show that energy-momentum tensor is covariantly conserved in this type of modified gravity theory.Comment: 7 page

Statistical stability and continuity of SRB entropy for systems with Gibbs-Markov structures

We present conditions on families of diffeomorphisms that guarantee statistical stability and SRB entropy continuity. They rely on the existence of horseshoe-like sets with infinitely many branches and variable return times. As an application we consider the family of Henon maps within the set of Benedicks-Carleson parameters

Microarray and morphological analysis of early postnatal CRB2 mutant retinas on a pure C57BL/6J genetic background

In humans, the Crumbs homologue-1 (CRB1) gene is mutated in progressive types of autosomal recessive retinitis pigmentosa and Leber congenital amaurosis. Th

Dendritic cell-specific deletion of β-catenin results in fewer regulatory T-cells without exacerbating autoimmune collagen-induced arthritis

Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The β-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of β-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of β-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgen

Crumbs2 mediates ventricular layer remodelling to form the spinal cord central canal

In the spinal cord, the central canal forms through a poorly understood process termed dorsal collapse that involves attrition and remodelling of pseudostratified ventricular layer (VL) cells. Here, we use mouse and chick models to show that dorsal ventricular layer (dVL) cells adjacent to dorsal midline Nestin(+) radial glia (dmNes+RG) down-regulate apical polarity proteins, including Crumbs2 (CRB2) and delaminate in a stepwise manner; live imaging shows that as one cell delaminates, the next cell ratchets up, the dmNes+RG endfoot ratchets down, and the process repeats. We show that dmNes+RG secrete a factor that promotes loss of cell polarity and delamination. This activity is mimicked by a secreted variant of Crumbs2 (CRB2S) which is specifically expressed by dmNes+RG. In cultured MDCK cells, CRB2S associates with apical membranes and decreases cell cohesion. Analysis of Crb2F/F/Nestin-Cre+/− mice, and targeted reduction of Crb2/CRB2S in slice cultures reveal essential roles for transmembrane CRB2 (CRB2TM) and CRB2S on VL cells and dmNes+RG, respectively. We propose a model in which a CRB2S–CRB2TM interaction promotes the progressive attrition of the dVL without loss of overall VL integrity. This novel mechanism may operate more widely to promote orderly progenitor delamination

Defining phenotype, tropism, and retinal gene therapy using adeno-associated viral vectors (AAVs) in new-born Brown Norway rats with a spontaneous mutation in Crb1

Mutations in the Crumbs homologue 1 (CRB1) gene cause inherited retinal dystrophies, such as early-onset retinitis pigmentosa and Leber congenital amaurosis. A Brown Norway rat strain was reported with a spontaneous insertion-deletion (indel) mutation in exon 6 of Crb1. It has been reported that these Crb1 mutant rats show vascular abnormalities associated with retinal telangiectasia and possess an early-onset retinal degenerative phenotype with outer limiting membrane breaks and focal loss of retinal lamination at 2 months of age. Here, we further characterized the morphological phenotype of new-born and adult Crb1 mutant rats in comparison with age-matched Brown Norway rats without a mutation in Crb1. A significantly decreased retinal function and visual acuity was observed in Crb1 mutant rats at 1 and 3 months of age, respectively. Moreover, in control rats, the subcellular localization of canonical CRB1 was observed at the subapical region in Muller glial cells while CRB2 was observed at the subapical region in both photoreceptors and Muller glial cells by immuno-electron microscopy. CRB1 localization was lost in the Crb1 mutant rats, whereas CRB2 was still observed. In addition, we determined the tropism of subretinal or intravitreally administered AAV5-, AAV9- or AAV6-variant ShH10(Y445F) vectors in new-born control and Crb1 mutant rat retinas. We showed that subretinal injection of AAV5 and AAV9 at postnatal days 5 (P5) or 8 (P8) predominantly infected the retinal pigment epithelium (RPE) and photoreceptor cells; while intravitreal injection of ShH10(Y445F) at P5 or P8 resulted in efficient infection of mainly Muller glial cells. Using knowledge of the subcellular localization of CRB1 and the ability of ShH10(Y445F) to infect Muller glial cells, canonical hCRB1 and hCRB2 AAV-mediated gene therapy were explored in new-born Crb1 mutant rats. Enhanced retinal function after gene therapy delivery in the Crb1 rat was not observed. No timely rescue of the retinal phenotype was observed using retinal function and visual acuity, suggesting the need for earlier onset of expression of recombinant hCRB proteins in Muller glial cells to rescue the severe retinal phenotype in Crb1 mutant rats.Ophthalmic researc

Star and Planet Formation with ALMA: an Overview

Submillimeter observations with ALMA will be the essential next step in our understanding of how stars and planets form. Key projects range from detailed imaging of the collapse of pre-stellar cores and measuring the accretion rate of matter onto deeply embedded protostars, to unravelling the chemistry and dynamics of high-mass star-forming clusters and high-spatial resolution studies of protoplanetary disks down to the 1 AU scale.Comment: Invited review, 8 pages, 5 figures; to appear in the proceedings of "Science with ALMA: a New Era for Astrophysics". Astrophysics & Space Science, in pres

Potassium acetate solution as a promising option to osmotic distillation for sour cherry (Prunus cerasus L.) juice concentration

Different osmotic agents (OA), such as potassium acetate (CH3COOK), potassium carbonate (K2CO3) and ammonium nitrate (NH4NO3), have been examined as alternatives to the traditionally used calcium chloride (CaCl2) for osmotic distillation concentrating of clarified and pre-concentrated sour cherry (Prunus cerasus L.) juice. Comparison of the process performances based on the permeate fluxes has been carried out. Regarding the permeate flux results, simplified estimation of the overall mass transfer coefficient of the most effective osmotic agent and the reference (CaCl2) solution has been also performed. Furthermore, analytical methods such as total antioxidant activity (TAA) and total polyphenolic content (TPC) using spectrophotometric assays have been also carried out to evaluate the effect of the osmotic distillation on the valuable compounds content of concentrated sour cherry juice. CH3COOK was found to be the most effective, resulted more than 25% higher permeate flux during the sour cherry juice concentration. K2CO3 and NH4NO3 were less effective. The simplified mass transfer estimation showed that the CH3COOK is more effective only at near saturated concentrations compared to the CaCl2. Regarding the TAA and TPC contents, a significant loss was found in case of all OAs during the concentration procedures