An immunofluorescence assay for extracellular matrix components highlights the role of epithelial cells in producing a stable, fibrillar extracellular matrix.

Activated fibroblasts are considered major drivers of fibrotic disease progression through the production of excessive extracellular matrix (ECM) in response to signals from damaged epithelial and inflammatory cells. Nevertheless, epithelial cells are capable of expressing components of the ECM, cross-linking enzymes that increase its stability and are sensitive to factors involved in the early stages of fibrosis. We therefore wanted to test the hypothesis that epithelial cells can deposit ECM in response to stimulation in a comparable manner to fibroblasts.

Characterization of the interaction of sclerostin with the low density lipoprotein receptor-related protein (LRP) family of Wnt co-receptors.

LRP5 and LRP6 are proteins predicted to contain four six-bladed β-propeller domains and both bind the bone-specific Wnt signaling antagonist sclerostin. Here, we report the crystal structure of the amino-terminal region of LRP6 and using NMR show that the ability of sclerostin to bind to this molecule is mediated by the central core of sclerostin and does not involve the amino- and carboxyl-terminal flexible arm regions. We show that this structured core region interacts with LRP5 and LRP6 via an NXI motif (found in the sequence PNAIG) within a flexible loop region (loop 2) within the central core region.

A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis.

Chronic inflammation leads to bone loss, and increased fracture rates have been reported in a number of human chronic inflammatory conditions. The study reported here investigates the skeletal effects of dosing a neutralizing antibody to the bone regulatory protein sclerostin in a mouse model of chronic colitis. When dosed prophylactically, an antibody to sclerostin (Scl-AbI) did not reduce the weight loss or histological changes associated with colitis but did prevent inflammation-induced bone loss.

Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.

The secreted glycoprotein sclerostin has recently emerged as a key negative regulator of Wnt signaling in bone and has stimulated considerable interest as a potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis. We have determined the structure of sclerostin, which resulted in the identification of a previously unknown binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells. We have also mapped the interaction site for an antibody that blocks the inhibition of Wnt signaling by sclerostin.

Wnt/beta-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor alpha.

The Wnt/beta-catenin pathway has been implicated in bone cell response to their mechanical environment. This response is the origin of the mechanism by which bone cells adjust bone architecture to maintain bone strength. Osteoporosis is the most widespread failure of this mechanism.

The in vitro effect of pH on osteoclasts and bone resorption in the cat: implications for the pathogenesis of FORL.

Dental disease due to osteoclast over-activity reaches epidemic proportions in older domestic cats and has also been reported in wild cats. Feline osteoclastic resorptive lesions (FORL) involve extensive resorption of the tooth leaving it liable to root fracture and subsequent tooth loss. The aetio-pathogenesis of FORL is not known.

Hypoxia induces giant osteoclast formation and extensive bone resorption in the cat.

Dental disease due to osteoclast (OC) overactivity reaches epidemic proportions in older domestic cats and has also been reported in wild cats. Feline odontoclastic resorptive lesions (FORL) involve extensive resorption of the tooth, leaving it liable to root fracture and subsequent loss. The etiopathogenesis of FORL remains unclear.

Osteocytes use estrogen receptor alpha to respond to strain but their ERalpha content is regulated by estrogen.

Unlabelled: The role of mechanical strain and estrogen status in regulating ERalpha levels in bone cells was studied in female rats. OVX is associated with decreased ERalpha protein expression/osteocyte, whereas habitual strain and artificial loading has only a small but positive effect, except on the ulna's medial surface, where artificial loading stimulates reversal of resorption to formation.

Introduction: Osteoporosis is the most widespread failure of bones' ability to match their architectural strength to their habitual load bearing.

Evidence that the canonical Wnt signalling pathway regulates deer antler regeneration.

Wnt signalling regulates many developmental processes, including the fate specification, polarity, migration, and proliferation of cranial neural crest. The canonical Wnt pathway has also been shown to play an important role in bone physiology and there is evidence for its recapitulation during organ regeneration in lower vertebrates. This study explores the role of the Wnt signalling pathway in deer antlers, frontal bone appendages that are the only mammalian organs capable of regeneration.

A feline assay using osteoclasts generated in vitro from peripheral blood for screening anti-resorptive agents.

Musculo-skeletal diseases are a major cause of pain and suffering in cats and several conditions involve increased bone resorption by osteoclasts. However, little is known about the biology of these cells in the cat. In this study we established a method to generate feline osteoclasts from blood mononuclear cells stimulated by macrophage colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL).

Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages.

Nitrogen-containing bisphosphonate drugs inhibit bone resorption by inhibiting FPP synthase and thereby preventing the synthesis of isoprenoid lipids required for protein prenylation in bone-resorbing osteoclasts. NE10790 is a phosphonocarboxylate analogue of the potent bisphosphonate risedronate and is a weak anti-resorptive agent. Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass approximately 22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298).

Fibrillar amyloid-beta production, accumulation, and recycling in transgenic mice pancreatic acinar cells and macrophages.

Amyloid-beta (A beta) production, accumulation, and recycling were examined by light and electron microscopy in the pancreas of transgenic mice (from 45 days to 22 months of age) that express the gene for the carboxy-terminal fragment of the human amyloid-beta protein precursor. Ultrastructural immunocytochemistry revealed four types of cells accumulating fibrillar A beta 1-40 in cytoplasmic vacuoles: acinar pancreatic cells, macrophages infiltrating stroma, epithelial cells of pancreatic ducts, and blood monocytes/macrophages in the lumen of pancreatic vessels. The ultrastructure of amyloid deposits suggests that each of these four types of cells produces fibrillar A beta.

Ultrastructure of myelinated fibers of sciatic nerve in acute vincristine intoxication.

Numerous clinical reports documented that in some patients vincristine (VCR) may cause a risk for life (stridor) and painful symptoms of acute intoxication. The present study was undertaken to examine ultrastructural changes in the sciatic nerve of rabbits following acute vincristine intoxication. Our results show, that in a few hours, some axons of this nerve may undergo degeneration and atrophy.

DNA fragmentation and ultrastructural changes in the brain of rabbits treated with vincristine.

Numerous anticancer drugs, which are in current use, have been shown to induce apoptosis in susceptible cells of some tissues. The aim of the study was to examine whether vincristine injected parenterally to rabbits may affect DNA and ultrastructure of cells in the brain. Vincristine 0.

Apoptosis, programmed cell death in the central nervous system.

Cell death by apoptosis occurs in a number of normal tissue systems including the nervous system. It is a highly specific process, which requires new gene expressions and the production of new proteins. The genetic information determines biochemical and morphological sequence of events in the cell undergoing apoptosis.

Ultrastructure of brain vessel in vincristine treated rabbits.

Ultrastructure of the brain blood vessels has been examined in rabbits treated with a single intraperitoneal injection of vincristine (VCR). The results provided evidence that some microvessels in these animals undergo vasoconstriction concomitant with projection of numerous endothelial microvilli into the vessel lumen. Vasoconstriction was followed by microvessel loss of regular shape and degeneration of some endothelial cells resulting in the digestion of apoptotic bodies by perivascular pericytes.

The features of peripheral nerve lesions in young and adult rabbits after vincristine administration.

The comparison of neuropathological picture of vincristine induced neuropathy immediately after the end of its administration and after three months of survival was performed. The adult rabbits and six litters of newborns received vincristine once a week in increasing doses 0.05-0.

Phagocytic activity of polymorphonuclear leukocytes lavaged from the lungs of horses with clinically diagnosed chronic pulmonary disease.

The aim of this study was to compare phagocytic activity of polymorphonuclear cells (PMNs) from the bronchoalveolar lavage of clinically healthy horses and those with severe chronic bronchiolitis. Research was carried out on 28 horses. Chronic inflammation of the lower airways was diagnosed in nine horses.

Ultrastructure of the Ranvier's node in vincristine neuropathy.

Paranode-node-paranode regions of the nerve fibre interact in a fundamental manner with the transport of axoplasmic material. The aim of the study was to examine the ultrastructure of Ranvier's node in sciatic nerve of rabbits treated with vincristine. The results showed accumulation of organelles in Ranvier's nodes of affected animals.

Neurotoxic effect of vincristine on ultrastructure of hypothalamus in rabbits.

The neurotoxic side-effects are a striking accompaniment of the therapy with vincristine (VCR). Data concerning the influence of VCR on the central nervous system are controversial. In the present study a schedule of VCR treatment was employed to develop the neurotoxic side effects in New Zealand rabbits.