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Study on the osteogenic differentiation of mesenchymal progenitor cells in vitroShui, Chaoxiang January 1999 (has links)
No description available.
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The study of RANK mutations associated with the diseases of osteoclast dysfunctionMellis, David January 2010 (has links)
Osteoclasts are the cells that resorb bone to maintain a healthy skeleton. Receptor activator of NFkB (RANK) is a receptor that is critical for the formation, activity and survival of osteoclasts. A number of mutations have been identified within RANK that cause bone diseases with opposite osteoclast phenotypes. The aim of this thesis was to study the downstream consequences of these disease-associated mutations for RANK protein processing and activation of the RANK signalling pathway. Early onset Paget’s disease of bone (ePDB), Familial Expansile Osteolysis (FEO) and Expansile Skeletal Hyperphosphatasia (ESH) are conditions featuring focal areas of increased bone resorption driven by overactive osteoclasts. These conditions are caused by heterozygous insertion mutations in the signal peptide region of the RANK gene, but the mechanisms underlying the development of overactive osteoclasts are not known. In this thesis, in vitro study of the mutant RANK proteins demonstrated that homozygous overexpression caused inactivation of RANK signalling due to intracellular accumulation of RANK within an extended form of the endoplasmic reticulum. By contrast, when expressed in a heterozygous manner, the mutant proteins were found at the plasma membrane and caused prolonged ligand-dependent signalling. Taken together and as predicted by the clinical situation, these data strongly suggest that heterozygous expression of the mutant RANK proteins hold the key to the hyperactive osteoclast phenotype associated with these diseases. Osteoclast-poor osteopetrosis is a disease in which osteoclasts do not form leading to a high bone mass phenotype. Single base pair mutations within RANK have been identified in some patients with this condition. These mutant RANK proteins were studied and the findings related to regions within RANK in which the mutations occur that have been shown to be critical for its function. In addition, osteoclast formation was assessed in cultures of peripheral blood mononuclear cells isolated from patients with osteopetrosis with unidentified genetic background in order to further characterise the osteoclast phenotype for each patient. In summary, the findings presented in this thesis begin to elucidate the molecular mechanisms leading to diseases of bone with opposite osteoclast phenotypes that, paradoxically, are all caused by inactivating mutations in the RANK gene.
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Visualisation of osteoclast membrane domainsWilkinson, Debbie Isabelle January 2010 (has links)
Osteoclasts polarise upon activation and form four distinct membrane domains; the basolateral domain, the sealing zone, the functional secretory domain and the ruffled border. The ruffled border is the resorptive organelle of the cell and provides a large surface area for the release of protons and enzymes into the space beneath the osteoclast. Defects in osteoclast formation or function can lead to diseases such as osteopetrosis. Ruffled border formation is a critical event in osteoclast function but the process by which it and other membrane domains form is only partially understood. Vesicular trafficking is essential for the tight regulation of the osteoclast membrane domains and it has been shown previously that treatment with pharmacological inhibitors causes disruption of trafficking. The aims of this PhD were to increase our understanding of vesicular trafficking in osteoclasts and to optimise ways of visualising osteoclast membrane domains. My studies of patients with osteoclast-poor osteopetrosis identified defects in RANKL as a cause of the defect. This in turn has identified a potential therapy of recombinant RANKL for patients with this form of the disease. Although purification of wild type or mutant RANKL was not completely successful, it did suggest that the mutant forms of RANKL were not functional. I have used pharmacological inhibitors to study osteoclast membrane domains, and found that transmission electron microscopy is an essential tool for studying membrane changes following pharmacological inhibition at the ultrastructural level. I also established that the study of vesicular trafficking to analyse formation of membrane domains can make excellent use of immuno-electron methods. Furthermore, genetic diseases associated with defective ruffled border formation such as XLA and osteopetrosis provide useful tools to further analyse the dynamics involved in the formation and maintenance of the ruffled border, as well as revealing more about the diseases themselves.
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Fat Bone Ratio: A New Measurement of ObesityBrown, Bryant 24 April 2017 (has links)
A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Importance: This study proposed a new radiographic measure of obesity that is a better
predictive indicator of obesity‐related risk: Fat/Bone Ratio. Primary Objective: Does the
Fat/Bone Ratio correlate with obesity. Secondary Objective: Does the Fat/Bone Ratio correlate
more closely with the comorbidities of obesity as compared to BMI. Design: Retrospective
review of 2703 upright posterior‐anterior (PA) and lateral chest radiographs obtained from June
2013 through May 2014. The soft tissue height overlying the acromioclavicular joint was
calculated and divided by the mid‐clavicle width to determine the Fat/Bone Ratio.
Comorbidities of obesity were determined through chart review. Setting: Adult community
emergency department. Participants: All adults (age greater than 18). Main Outcomes and
Measures: BMI, Fat/Bone Ratio, comorbidities: hypertension, obstructive sleep apnea,
osteoarthritis, hyperlipidemia, atherosclerosis, coronary artery disease, cerebrovascular
accident, and myocardial infarction. Results: Fat‐to‐Bone ratio and BMI were both significantly
associated with hypertension, diabetes, hyperlipidemia, obstructive sleep apnea, and
osteoarthritis (P < .05). However, only Fat/Bone Ratio is associated with atherosclerosis (p =
0.02), coronary artery disease (p = 0.001), myocardial infarction (p = 0.002), and peripheral
vascular disease (p = 0.01); BMI is not associated with these comorbidities (p = 0.90, 0.42, 0.25, and 0.50, respectively). Conclusions and Relevance: Findings suggest that Fat/Bone Ratio is an improved measure of obesity as compared to BMI.
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Bone diagenesis : an experimental study of selected trace elementsElliott, Tracey Anne January 1993 (has links)
No description available.
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The identification and palaeoeconomic context of prehistoric bone marrow and grease exploitationOutram, Alan Keith January 1998 (has links)
No description available.
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Genetic factors influencing bone health in the black South African populationMay, Andrew January 2012 (has links)
A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg,
in fulfilment of the requirements for the degree of Master of Science (Medicine) in Human Genetics / Maintaining suitable bone health is emerging as a serious point of concern worldwide, as the prevalence of skeletal disorders threatens to reach unmanageable proportions. Despite unfavourable environmental factors, black South Africans demonstrate elevated bone mass, especially at the femoral neck, when compared to whites. Genetic factors are thought to mediate this effect, which may have clinical or therapeutic value. Using a candidate gene approach, this study investigated associations of six candidate genes (ESR1, TNFRSF11A, TNFRSF11B, TNFSF11, SOST and SPP1) with bone mineral content amongst pre-pubertal black South African children that formed part of the longitudinal Birth to Twenty cohort. The GoldenGate genotyping assay with VeraCode microbeads was used to genotype 151 black children at 366 polymorphic loci, including 112 previously associated and 254 tagging SNPs. A linear regression approach was implemented to highlight significant associations whilst adjusting for height, weight, sex and bone area. Twenty seven markers (8 previously associated and 19 tag SNPs; P <0.05) were found to link to either femoral neck (18) or lumbar spine (9) BMC. These signals derived from three genes, namely ESR1 (17), TNFRSF11B (9) and SPP1 (1). One marker (rs2485209) maintained its association with the femoral neck after correction for multiple testing (P = 0.038). These results fully support the existence of a strong genetic effect acting at the femoral neck in African ancestry individuals. Tagging SNP signals suggest the presence of a number of population specific variants that require further investigation. Combined, these markers may help to account for increased bone mass amongst black South Africans, when adjusted for covariates.
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Signal transduction pathways controlling the induction of bone formation by macroporous biomimetic matricesKlar, Roland Manfred 27 March 2015 (has links)
In spite of vigorous research efforts to date the induction of bone formation by
macroporous coral-derived constructs when implanted heterotopically in the rectus
abdominis muscle of the non-human primate Chacma baboon Papio ursinus has not yet
been resolved and needs to be assigned. More importantly, the apparent redundancy of
molecular signals singly initiating the induction of bone formation in primate species and
the heterotopic induction of endochondral bone formation by the mammalian recombinant
human transforming growth factor –β3 (rhTGF-β3) isoform have not yet been assigned and
need to be mechanistically resolved. Using the rectus abdominis muscle of Papio ursinus
the study sought to molecularly determine how coral-derived macroporous constructs and
doses of the hTGF-β3 isoform initiate the induction of bone formation. To elucidate the
function of osteoclastogenesis and Ca2+, biomimetic coral-derived 7%
hydroxyapatite/calcium carbonate (7% HA/CC) devices were supplemented either with
240 μg zoledronate bisphosphonate, an osteoclast binding antagonist, or 500 μg of the
calcium channel blocker verapamil hydrochloride. Additionally but in separate coralderived
bioreactors, 125 μg rhTGF-β3 and/or 125 μg hNoggin were added to answer the
question of how TGF-β3 induces bone formation. All devices were then subsequently
implanted within heterotopic sites of the rectus abdominis muscle of 6 Papio ursinus and
left in vivo for 15, 60 and 90 days. Harvested specimens were subjected to
histomorphometrical and quantitative reverse transcription polymerase chain reaction
(qRT-PCR) analysis. Collagen Type IV expression supported by extensive vascularisation
was detected and observed respectively in all implants after 15 days in vivo. Importantly
the zoledronate treated specimens possessed delayed tissue patterning and morphogenesis,
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Bone mineral density and use of depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) and combined oral contraceptivesBeksinska, Malgorzata Elzbieta 28 September 2010 (has links)
PhD, Faculty of Health Sciences, University of the Witwatersrand / Many studies have shown a negative effect of depot-medroxyprogesterone acetate
(DMPA) hormonal contraception on bone mineral density (BMD) in women. There is
limited information on the effect of norethisterone enanthate (NET-EN) on BMD and
the effect of combined oral contraceptives (COCs) on BMD is inconclusive, however
emerging evidence is showing that low-dose COCs maybe detrimental to BMD in young
women. The aim of this research was to evaluate, in a 5-year follow-up study, the
possible effect of DMPA, NET-EN and COCs on BMD among young (15-19 years) and
older (40-49 years) South African women.
Method: This prospective study was conducted at the Commercial City Family Planning
clinic in Durban, South Africa between 2000 and 2007. In the adolescent group women
with no history of hormonal contraception who were initiating use of DMPA (n=115),
NET-EN (n=115) or COCs (n=116) and 144 nonuser controls were recruited. In the older
group, one hundred and twenty seven users of DMPA, 102 NET-EN users and 106 COC
users of at least one year were compared to 161 nonuser controls. BMD was measured at
the distal radius and midshaft of the ulna using dual x-ray absorptiometry. In the crosssectional
component of the study conducted at the end of the longitudinal phase, BMD
was measured at the hip, spine and femoral neck in a sub-group of 96 of the younger
women.
Results: In the longitudinal study of adolescents, BMD increased in all four groups
during follow-up (p<.001). There was evidence for lower BMD increases per annum in NET-EN (p=.050) and COC (p=.010) users compared to nonusers but no difference
between DMPA and nonusers (p=.76). In 14 NET-EN discontinuers, an overall reduction
of 0.61% per year BMD was followed, upon cessation, by an increase of 0.69% per year
(p=.066). The cross-sectional sub-study found that young women in the injectables-only
user group had lower BMDs compared to the non-user group after adjusting for BMI at
the spine (p=0.042), hip (p=0.025), and femoral neck (p=0.023). The mixed
COC/injectable user group BMD values were lower than controls; however, they were
not significant at any of the three sites.
In the older women, there was no significant difference in radius BMD between the
contraceptive user groups and the non-user controls (p=.26) with and without adjustment
for age at baseline, or after two and a half years of follow-up (p=0.52).
Conclusion: This study suggests that BMD increases in adolescents may be less in NETEN
and COC users; however, recovery of BMD in NET-EN users was found in the small
sample of adolescents followed post-discontinuation. The cross-sectional sub-study
showed similar findings in long-term injectable users, but not when women had mixed
injectable and COC use. There was no evidence that long-term use of DMPA, NET-EN
and COCs affected BMD in the older women.
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Synergistic induction and temporal enhanement of bone formation by osteogenic protein-1 (OP-1) and transforming growth factor beta-1 (TGF-B1) combinations in ratsMatsaba, Thato Nelly 22 May 2014 (has links)
Several members of the bone morphogenetic protein/osteogenic protein (BMP/OP)
and transforming growth factor beta (TGF-B) families are molecular regulators o f
cartilage and bone regeneration. However, their precise mode o f signal transduction
and combined interactions are poorly understood. The presence of several molecular
forms o f these growth factors suggests multiple functions in vivo as well as
synergistic interactions during both embryonic bone development and regeneration
o f cartilage and bone in postnatal life. A functional bioassay for identification of
osteogenic proteins within the bone matrix has been established. The heterotopic
bioassay in rats, together with the improved purification methods, has led to the
purification o f native BMPs. In rats, heterotopic and orthotopic implantation o f TGF-
13 singly fails to initiate new bone formation whereas implantation o f BMPs/OPs
elicit the local differentiation o f new bone, at both sites.
This study presents data which shows that co-administration of TGF-B1 with OP-1
delivered by a collagenous carrier, and implanted in the subcutaneous site o f rats
results in synergistic induction o f bone formation. Changes in hist-logical,
biochemical and molecular response o f the effects o f the morphogens were vu bed
over 7, 12 and 21 days post implantation. Induced cartilage and bone were analyzed
by alkaline phosphatase activity, calcium content, Northern blots and histological
examination of subcutaneous implants in the rats.
Single applications o f TGF-B1 (0.01pg, 0.03pg and O.lpg) on days 7, 12 and 21 gave
rise to negligible alkaline phosphatase activity (0.03-0.09 U/ mg protein) and
calcium content (0.05-0.6 pg/mg tissue). Histological examination showed that all
TGF-B1 implants did not exhibit any sign o f bone formation.
On day 7, OP-1 implants (O .lpg and 0.3 pg) elicited negligible alkaline phosphatase
activity and calcium content. However, higher doses o f OP-1 (1 pg and 3 pg) elicited
alkaline phosphatase activity o f 0.1 U/mg protein and 0.2 U/mg protein.
Combination TGF-Bl (O.Olpg, 0.0.3pg and O.lpg) with OP-1 (O.lpg, 0.3pg, Ip g and
3pg) slightly increased the activity o f alkaline phosphatase activity (0.2 U/mg
protein-0.4 U/mg protein). OP-1 singly gave rise to very low calcium levels o f 0.4
pg/mg tissue to 0.5 pg/mg tissue. Addition o f TGF-Bl to OP-1 resulted in calcium
content rising from 0.2 to 1 pg/mg tissue. Histologically, the specimens o f single
OP-1 applications did not show any sign o f bone formation. On addition o f TGF-Bl
to OP-1 the specimens showed signs o f the beginning o f chondroblastic
differentiation.
On day 12 alkaline phosphatase activity elicited by single applications o f OP-1
ranged from 0.1 U/mg protein to 1 U/mg protein. Addition of l i , : 7- Bl increased the
alkaline phosphatase from 0.8 U/mg protein to 7 U/mg protein. Calcium levels
resulting from single applications of OP-1 ranged from 0.1 to 15 pg/mg tissue Auer
addition of TGF-Bl to OP-1 calcium levels rose from 5 to 20 pg/mg tissue.
Histological analysis showed formation o f cartilage in specimens both of OP-1 solo
and OP-1 in combination with TGF-B1.
On day 21 alkaline phosphatase activity was reduced to a range o f 0.1-0.5 U/mg
protein upon single applications o f OP-1. Addition TGF-131 resulted in a further
decrease in alkaline phosphatase activity. Calcium levels were 10-68 jag/mg tissue on
single applications o f OP-1. Addition o f TGF-131 to OP-1 increased the calcium
levels in the range o f 2-70 gg/mg tissue. Histological examination o f the 3 jig OP-1
solo specimens showed complete chondrolysis whereas the OP-1 (3|ig)/ TGF-B1
(0.03 and 0.1 gg) specimens showed the differentiation o f bone marrow.
Tissues generated in the rat subcutaneous space at 7, 12 and 21 days post
implantation elicited mKNA expression o f OP-1, BMP-3 and TGF-B1. These results
indicate that at least in part, the matrix-induced endochondral bone formation
involves the expression o f some members o f the TGF-B superfamily. Type II
collagen (chondrogenesis marker) and type IV collagen (angiogenesis marker)
mRNAs were also detected on days 12 and 21, respectively.
The present data suggests that TGF-B up regulates the temporal activity o f OP-1 to
induce bone formation. Co-administiation of TGF-B 1 to OP-1 caused an increase in
the alkaline phosphatase activity and calcium content, markers o f bone formation,
which implies that when TGF-B is mixed with OP-1, the cascade o f bone formation
is accelerated. These results may have important therapeutic implications. The
rapidity o f tissue morphogenesis with bone marrow formation is important for
regeneration o f bone in older patients where repair phenomena are temporally
delayed and the healing process is slower than in younger patients. The expression of
multiple members o f the TGF-13 superfamily indicates that the cascade of bone
formation incorporates some members o f the TGF-B superfamily and this may form
the basis for synergistic molecular therapeutics for cartilage and bone regeneration in
clinical contexts.
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