3,222 research outputs found
Colin Humphris
No full text"Colin Humphris 2 Sqdrn. RAAF. 1941 - 1942 Author of - 'Trapped on Timor' (as a result of bombing of Darwin Feb. 19, 1942)".Colin Humphris. 2 Squadron, Royal Australian Air Force 1941 - 1942. Author of - 'Trapped on Timor' (as a result of bombing of Darwin February 19, 1942)
Cartilage development and degeneration:a Wnt Wnt situation
Full text linkMatrix Extracellular Phosphoglycoprotein (MEPE) is a member of a family of
proteins called small integrin-binding ligand, N-linked glycoproteins (SIBLINGs)
which play key roles in biomineralisation. Altered MEPE expression is associated
with several phosphate and bone-mineral metabolic disorders such as oncogenic
osteomalacia and hypophosphatemic rickets. Despite this, it remains undetermined
what impact MEPE has on the growth plate; the cartilage anlagen from which
endochondral ossification, the process responsible for linear bone growth, occurs.
The work of this thesis has characterised the ATDC5 cell line and the metatarsal
organ culture as useful in vitro models of endochondral ossification. These will
prove vital in the pursuit of underpinning the molecular mechanisms involved in
endochondral bone growth. These models form the basis of the further studies in
this thesis examining the role of MEPE within this highly orchestrated process.
Before such role can be defined, this thesis details the spatial and temporal
localisation patterns of MEPE in 10-day- and 4-week-old murine growth plates.
More specifically, MEPE protein and mRNA were preferentially expressed by the
hypertrophic chondrocytes as shown by immunohistochemistry and in situ
hybridisation respectively. Microdissection of the murine growth plate confirmed
this. Localisation of the cleavage product of MEPE, a 2.2kDa acidic serine- and
aspirate-rich motif (ASARM) peptide, followed a similar pattern of expression.
The localisation of MEPE to sites of mineralisation serves to strengthen its potential
role in chondrocyte matrix mineralisation. This thesis identified this role in both
mineralising ATDC5 cells and the metatarsal organ culture. The ASARM peptide
was found to be the functional component of MEPE and this function was
dependent upon its post-translational phosphorylation. Phosphorylated (p)ASARM
peptides significantly inhibited chondrocyte matrix mineralisation without altering
the proliferation or differentiation of the chondrocyte cells, or their ability to
produce an extracellular matrix. mRNA analysis by qPCR indicted a feedback
system by which the pASARM peptide functions to allow the release of further
ASARM peptides. Moreover, the pASARM peptide inhibited mRNA expression of
markers of vascular angiogenesis highlighting a novel mechanism by which they
may inhibit chondrocyte matrix mineralisation.
This thesis also determines the regulatory cross-talk between the chondrocytes of
the murine growth plate, with the most abundant bone cell type, the osteocyte. This
cross-talk inhibits chondrocyte matrix mineralisation and is attributed to sclerostin,
an osteocyte-specific secretory protein. Furthermore, it is shown that sclerostin acts
through the MEPE-ASARM axis to regulate chondrocyte matrix mineralisation and
thus endochondral ossification.
The work described herein has characterised and validated in vitro models of
growth plate chondrocyte matrix mineralisation and has used these to identify the
role of MEPE within chondrocyte matrix mineralisation
Interview with Colin Wilson, part 4, undated
No full textInterview with Colin Wilson, part 4, features an interview with author Colin Wilson in which he discusses his views regarding society and art, his reclusive nature, and the intellectual and fantastical elements of his works, undated
Interview with Colin Wilson, part 2, undated
No full textInterview with Colin Wilson, part 2, features an interview with author Colin Wilson in which he discusses his views regarding society and art, his reclusive nature, and the intellectual and fantastical elements of his works, undated
Providence College Faculty Author Series 2017-2018: D. Colin Jaundrill
No full textIn this installment of the Faculty Authors Series, D. Colin Jaundrill (History, Providence College) discusses his newest book, Samurai to Soldier: Remaking Military Service in Nineteenth-Century Japan
Providence College Faculty Author Series 2017-2018: D. Colin Jaundrill
Full text linkIn this installment of the Faculty Authors Series, D. Colin Jaundrill (History, Providence College) discusses his newest book, Samurai to Soldier: Remaking Military Service in Nineteenth-Century Japan
Interview with Colin Jerolmack
No full textColin Jerolmack is an Assistant Professor at New York University
in Sociology and Environmental Studies. He is the author of The
Global Pigeon (forthcoming) and an alumnus of the Robert Wood
Johnson Foundation Scholars in Health Policy Program at Harvard
University
Effects of FGF-2 on E11-mediated osteocytogenesis in skeletal health and disease
Full text linkFibroblast growth factor 2 (FGF-2) is known to be released from cartilage upon injury
and is able to influence chondrocyte gene expression in vitro. In cartilage, FGF-2
regulates E11/podoplanin expression in murine joints following surgical
destabilisation (DMM model of osteoarthritis (OA)), and in cartilage explant injury
models. In bone, E11 is critical for the early stages of osteocytogenesis and is
responsible for the acquisition of the osteocyte dendritic phenotype. This dendritic
phenotype is dysregulated in OA and given the known role of the osteocyte in
controlling bone remodelling, this may contribute to the subchondral bone thickening
observed in OA. Hence, the aim of this study was to elucidate the nature of FGF-2-
mediated E11 expression and osteocytogenesis in skeletal health and disease.
This thesis has shown that FGF-2 dose-dependently increased E11 mRNA expression
in MC3T3 cells, primary osteoblasts and in primary calvaria organ cultures, which
was confirmed by E11 protein western blotting data. The FGF-2 induced changes in
E11 expression were accompanied by significant increases in the mRNA expression
of the osteocyte markers Phex and Dmp1, and significant decreases in the mRNA
expression of the osteoblast markers Col1a1, Postn, Bglap and Alpl expression. This
thus supports the hypothesis that FGF-2 drives osteocytogenesis.
The acquisition of osteocyte phenotype involves the re-organisation of the
cytoskeleton, such as F-actin. This step is important for the transition of cuboidal-shaped
osteoblasts to the stellate-shaped osteocyte phenotype. FGF-2 stimulation of
MC3T3 cells and primary osteoblasts revealed more numerous and longer dendrites,
as visualised by phalloidin staining for F-actin and indicative of the acquisition of the
osteocyte phenotype. In contrast, control cells had a typical rounded morphology
with fewer and shorter dendrites. Furthermore, immunofluorescence labelling for
E11 in control cells revealed uniform distribution throughout the cytoplasm,
especially in the perinuclear region. In contrast, FGF-2 treated cells showed a
modified distribution where E11 was negligible in the cytoplasm, but concentrated in
the dendrites. The use of siRNA knockdown of E11 achieved a 70% reduction of basal
E11 mRNA expression. This knockdown also effectively abrogated FGF-2-related
changes in E11 expression and dendrite formation as disclosed by mRNA and protein
expression, immunofluorescence and F-actin staining with phalloidin. Despite these
FGF-2 driven increases in E11 and osteocyte dendrite formation in vitro,
immunohistochemical labelling revealed no differences in E11 expression in
subchondral, trabecular and cortical osteocytes from naïve Fgf-2 deficient mice in
comparison to wild-type mice. Similar results were observed upon sclerostin
immunolabelling.
FGF-2 stimulation of MC3T3 cells elicited activation of ERK1/2, Akt and p38 MAPK.
However, inhibition of the aforementioned pathways failed to reduce FGF-2-
mediated E11 expression and as such, the specific signalling pathway responsible
remains unclear. Upstream, the expression of Fgfr1 was increased (>10-fold) over 24
h time point, while a reduction was seen in Fgfr2/3 expression over same time point
especially in the FGF-2 treated cultures. This suggests that increased E11 expression
and the acquisition of the osteocyte phenotype may be speculatively though
upregulation of Fgfr1. The expression of E11 and sclerostin in OA pathology in mice, human and dogs were
investigated. Initially sequence homology using the Clustal Omega alignment
program showed both proteins to be homologous in the domestic animals under
study. A comparative study using canine subchondral bone osteocytes revealed
increased E11 expression in the OA samples relative to the control. This feature may
be related to newly embedded osteocytes during sclerosis. However, E11 and
sclerostin were unchanged in both murine (DMM) and human OA subchondral bone
osteocytes in comparison to controls. In mice, this may be due to limited OA
development; whilst in humans the sample size, age, stage of the disease and sourcing
from same diseased joint may be important in the interpretation of the results.
The expression of E11 and sclerostin during OA pathology was also investigated in
Fgf-2 deficient mice in which OA was induced using the DMM model. There was no
difference in E11 expression between the OA and control (sham-operated) samples,
suggesting that compensation of E11 expression may be mediated by growth factors
from the FGF family. Surprisingly, increased E11 expression was observed in the
control Fgf-2 deficient mice, in comparison to the wild-type control mice. This
suggests a potential adjustment to loading by the contralateral knee, as this was not
observed in naïve mice from both groups.
Together, these data show that FGF-2 promotes the osteocyte phenotype, and that
this is mediated by increased E11 expression. These results may help explain (1) the
altered osteocyte phenotype and (2) increased subchondral bone thickening observed
in OA. This knowledge will be of interest in the search for disease modifying
therapeutics for skeletal health, including OA and osteoporosis
Colin Fraser
No full textPhotograph - Colin Fraser (third from right) in a loaded scow leaving for Fort Chipewyan from Athabasca, Alberta. A group of men are also standing on the pie
Characterisation of matrix vesicles in skeletal and soft tissue mineralisation
Full text linkAbstractThe importance of matrix vesicles (MVs) has been repeatedly highlighted in the formation of cartilage, bone, and dentin since their discovery in 1967. These nano-vesicular structures, which are found in the extracellular matrix, are believed to be one of the sites of mineral nucleation that occurs in the organic matrix of the skeletal tissues. In the more recent years, there have been numerous reports on the observation of MV-like particles in calcified vascular tissues that could be playing a similar role. Therefore, here, we review the characteristics MVs possess that enable them to participate in mineral deposition. Additionally, we outline the content of skeletal tissue- and soft tissue-derived MVs, and discuss their key mineralisation mediators that could be targeted for future therapeutic use
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