Parathyroid hormone (PTH) analogs are the main anabolic pharmacological agent for osteoporosis. PTH is an endogenous hormone, of which amino acids 1-34 bind the parathyroid hormone receptor (PTH1r), a G-coupled protein receptor expressed in kidney, fat, and bone. PTH increases trabecular bone mass by promoting the differentiation of the mesenchymal stem cell (MSC) into the osteogenic lineage. The Zinc Finger Protein 467 (Zfp467) is a potential downstream target of PTH1r and an important mediator of the MSC into the adipogenic lineage. Taken together, we ask whether Zfp467 knockout cells will show greater osteogenic potential and increased sensitivity to PTH treatment. We also seek to investigate a mechanistic signaling pathway of PTH1r involving Zfp467. Calvarial osteoblast (COB) and bone marrow stromal cells (BMSCs) from Zfp467 wild type (WT) and knockout (KO) mice were osteogenically differentiated and treated with either continuous (48h) or intermittent (6h/42h) PTH for 7-14 days. At 7 and 14 days, alkaline phosphatase (ALP) and von Kossa staining were conducted, respectively. At 7 days after differentiation, qPCR was used to analyze genes involved in osteogenesis, adipogenesis, WNT signaling, and mitochondrial respiration. ELISA was used to measure cAMP levels. Seahorse XF96 assays were used to measure oxygen consumption rates (OCRs) and extracellular acidification rates (ECARs). Western blot was used to measure PTH1r. Additionally, adipogenic differentiation and Oil Red O staining were performed on BMSCs. ALP and von Kossa results showed that Zfp467 KO cells exhibited increased osteogenesis and an increased response to PTH treatment (continuous and intermittent) as compared to WT controls. qPCR analysis of Alp, Rankl, and Sp7 further supported an increased osteogenic potential of the KO. Also, Oil Red O staining revealed suppressed adipogenesis in KO BMSCs and qPCR analysis showed suppressed Adiponectin and Ppary in KO COBs. Additionally, Pth1r and PTH1r expressions were significantly higher in KO and short PTH treatments (~10m) induced a remarkable reduction in Zfp467 of WT cells. Furthermore, the KO showed suppressed Pgc1a, similar OCR, and increased ECAR as compared to WT. The KO also exhibited higher cAMP levels and was more responsive to PTH-induced increases of cAMP at 10 minutes of PTH exposure. However, qPCR analysis of Lef1 and Sost showed no difference regarding the WNT pathway. Our data support an anti-osteogenic and pro-adipogenic role for Zfp467. The KO displays less adipogenesis, more osteogenesis, and is consistently more sensitive to the osteogenic effects of PTH. The upregulation of Pth1r and PTH1r in KO cells offers an explanation for this increased sensitivity. We propose a mechanism where the suppression of Zfp467 upregulates Pth1r and PTH1r activation suppresses Zfp467, resulting in a constitutively active positive feedback loop. Further still, the KO shows potentially suppressed mitochondrial biogenesis (through Pgc1a analysis), similar oxidative phosphorylation (through OCRs), increased glycolysis (through ECARs), and increased PKA signaling (through cAMP assays), yet their exact connections to the PTH1r-Zfp467 signaling pathway have yet to be investigated.

Muscle and bone are two tightly connected systems on both an anatomic and functional level. Bone and muscle diseases like osteoporosis and sarcopenia have been found to show an association with each other. These two organs form a complex musculoskeletal system and have been found to secrete hormone-like factors called myokines and osteokines that can influence and affect each other. Indeed, the crosstalk between bone and muscle plays an important role during development and aging. For example, myostatin, also known as growth differentiation factor 8 (GDF-8), a cytokine secreted by muscle cells, is a negative regulator of muscle and bone mass. Over expression or loss of function mutations of myostatin in mice have led to muscle atrophy and hypertrophy respectively. Interleukin-6 (IL-6) is expressed abundantly in muscle and is released during exercise and muscle contraction. It has been shown to increase osteoclast (bone cells that break down bone) formation. In the bone, osteocytes make up the majority of all cells and are terminally differentiated osteoblasts. Osteocytes control the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Osteocytes are also known to express receptors for various hormones, including parathyroid hormone (PTH) receptor. As osteocytes comprise more than 90% of all bone cells in adult bone, we hypothesize that osteocytes might secrete factors capable of controlling muscle cells and that PTH might control the expression of these factors. To test this hypothesis, we used an osteocytic cell line Ocy454-12H as well as C2C12 cells, which are a well-accepted model of myocyte differentiation. To investigate the effects of osteocyte-derived factors on myocytes, C2C12 cells were treated with conditioned medium (CM) from osteocytes during specific times. We found that during C2C12 proliferation, when compared to the αMEM control, mRNA expression of MSS51 was decreased for both cells that were treated with CM of osteocytes treated with PTH (PTH CM, p=0.00570) and cells that were treated with CM of osteocytes treated with vehicle only (CM control, p=0.0178). During C2C12 differentiation, mRNA expression of myostatin was significantly (p=0.0387) decreased in cells that were treated with PTH CM compared to cells that were treated with CM control. Considering the importance of mitochondrial respiration in cells, we next analyzed oxygen consumption and metabolism in C2C12 myocytes treated with CM from Ocy454-12H using a Seahorse XF Cell Mito Stress Test. Metabolic analysis revealed that during proliferation, PTH CM led to higher basal respiration, ATP production, and coupling efficiency in C2C12 cells while lowering spare respiratory capacity. In differentiation, there was a trend in which CM control would cause a decrease across all parameters compared to the control group and the PTH CM group. Interestingly, PTH CM-treated C2C12 cells were shown to have a higher oxygen consumption rate (OCR) than the CM-control treated group and would have similar values to that of the control group (C2C12 not treated with CM). Taken together these results suggest that osteocytes might control muscle cells differentiation and metabolism via a PTH-mediated signaling pathway.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-04-11T13:23:32Z No. of bitstreams: 1 paulalouresvallelima.pdf: 2215122 bytes, checksum: 6bfc8aad26ec65c1662489f3446eaeb8 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-04-24T03:37:54Z (GMT) No. of bitstreams: 1 paulalouresvallelima.pdf: 2215122 bytes, checksum: 6bfc8aad26ec65c1662489f3446eaeb8 (MD5) / Made available in DSpace on 2016-04-24T03:37:54Z (GMT). No. of bitstreams: 1 paulalouresvallelima.pdf: 2215122 bytes, checksum: 6bfc8aad26ec65c1662489f3446eaeb8 (MD5) Previous issue date: 2013-04-04 / Atualmente, a insuficiência e deficiência de vitamina D tem sido considerada um problema de saúde pública no mundo todo, em razão de suas implicações no desenvolvimento de diversas doenças, entre elas, o diabetes melito tipo 2, a obesidade, hipertensão arterial, osteoporose, osteomalácia. Na população pediátrica, a vitamina D é importante no processo de desenvolvimento e mineralização óssea. Nesta fase o tecido osseo atinge sua quantidade máxima, assim a vitamina D é considerada um fator predominante para o risco de fratura na senescência. O objetivo do trabalho foi avaliar a ingestão e níveis séricos da vitamina D em adolescentes saudáveis do sexo feminimo da idade de 15-18 anos, bem como, os fatores que podem influenciar a concentração de vitamina D: adiposidade, exposição ao sol, aplicação de filtro solar, atividade fisica. Além disso, foi avaliado a correlação dos níveis séricos de vitamina D e ingestão de vitamina D com os dados bioquímicos, pressão arterial, e com os fatores importantes para a manutenção de níveis adequados de vitamina D. A amostra constituiu de 69 alunas com idade média de 16,35. Avaliou-se dosagens bioquímicas (25-Hidroxivitamina D, paratormônio sérico, glicemia, cálcio total, fosfatase alcalina, transaminase glutâmica oxalacética, transaminase glutâmico pirúvica, creatinina, fósforo), ingestão alimentar (diário alimentar de 3 dias), realização de atividade física ( questionário estipulado por Florindo et al), análises antropométricas (peso, altura, IMC, gordura corporal), aferição da pressão arterial. Foi encontrado que 63,8% das adolescentes apresentavam hipovitaminose D. Apenas 7,24% das meninas ingerem quantidades adequadas de vitamina D. Foi observado uma relação inversamente proporcional entre PTH e os níveis séricos de vitamina D. Não foi encontrado nenhuma correlação entre os níveis séricos de vitamina D com medidas antropométricas, utilização de filtro solar, exposição ao sol, nível de atividade física, e ingestão de nutrientes (vitamina D, cálcio, fósforo). Houve uma relação inversamente proporcional entre a ingestão de vitamina D e níveis séricos de cálcio. Foi encontrado também uma correlação inversa entre a ingestão de cálcio e PTH. O estudo demonstrou uma alta incidência de hipovitaminose D nos adolescentes do sexo feminino e grande parte das adolescentes não ingerem quantidades adequadas de vitamina D. Os baixos níveis séricos de vitamina D pode ocasionar um aumento de PTH, podendo no futuro acarretar um hiperparatireodismo secundário. Uma ingestão adequada de vitamina D proporciona uma absorção satisfatória de cálcio e consequentemente uma mineralização óssea adequada. Além disso, o estudo mostrou que uma ingestão satisfatória de cálcio e importante para a manutenção da função da paratireoide. / The insufficiency and deficiency of vitamin D has been considered a public health problem worldwide, in reason of its implications in the development of several diseases, among them diabetes mellitus type 2, obesity, arterial hypertension, osteoporosis, osteomalacia. In the pediatric population, vitamin D is important in development and bone mineralization. In these individuals, the bone tissue reaches its maximum amount, so vitamin D is considered a predominant factor for fracture risk in senescence. The objective of this study was to evaluate the intake and serum levels of vitamin D in healthy female adolescent of the age of 15-18 years, as well as the factors that may influence the concentration of vitamin D: adiposity, sun exposure, applying sunscreen, physical activity. Furthermore, we evaluated the correlation of serum vitamin D and vitamin D intake with biochemical data, blood pressure, and the important factors for the maintenance of adequate levels of vitamin D. The sample consisted of 69 students with an average age of 16.35. We evaluated biochemical dosages (25-hydroxy-vitamin D, parathyroid hormone, serum glucose, total calcium, alkaline phosphatase, glutamicoxaloacetic transaminase, glutamic pyruvic transaminase, creatinine, phosphorus), food intake (three-day dietary records), conducting activity physical (questionnaire stipulated by Florindo et al), analyzes anthropometric (weight, height, BMI, body fat), blood pressure measurement. It was found that 63.8% of adolescents had hypovitaminosis D. Only 7.24% of girls ingest adequate amounts of vitamin D. We observed an inverse relationship between PTH and serum levels of vitamin D. We found no correlation between serum levels of vitamin D with anthropometric measurements, use of sunscreen, sun exposure, physical activity, and intake of nutrients (vitamin D, calcium, phosphorus). There was an inverse relationship between vitamin D intake and serum calcium levels. We also found an inverse correlation between the intake of calcium and PTH. The study demonstrated a high incidence of hypovitaminosis D in female adolescents and most of the teenagers do not ingest adequate amounts of vitamin D. The low serum levels of vitamin D can lead to increased PTH and may in the future cause a secondary hyperparathyroidism. Adequate intake of vitamin D provides a satisfactory absorption of calcium and consequently a proper bone mineralization. Furthermore, the study showed that a satisfactory intake of calcium is important to maintain parathyroid function.

Background In South Africa, as in many other developing countries, obesity has become a major health problem causing an increase in the incidence and prevalence of various non-communicable diseases. Research has shown that excess adiposity is associated with low vitamin D status and detrimental to bone health. Low vitamin D status has been linked to various non-communicable diseases which includes osteoporosis, and also the metabolic syndrome. Information is scarce on the role of lean mass and fat mass on bone health in the black South African population. There is also a shortage of data on the association between vitamin D status and the metabolic syndrome in the South African population. Aim The main aim of this study was to examine factors (vitamin D status, socio-economic status [SES] and lifestyle risk factors) associated with body composition, including bone health, as well as predictors of change in body composition in African adults in the North West Province of South Africa. Methods The first study that forms part of this thesis was a longitudinal study aimed at examining the effects of urbanization, socio-economic status and lifestyle factors on changes in body composition over 5 years in rural and urban black South African adults. A total of 1058 men and women above age 30 years from the Prospective Urban Rural Epidemiology study were included in this study. The second study to form part of this thesis aimed to examine the association between body composition and bone health in urban black South African women. Structured questionnaires were used to collect socio-demographic and lifestyle information including medication and tobacco use. This second study is cross-sectional in design and it included 189 postmenopausal women aged > 43 years old. Dual X-ray absorptiometry was used to assess bone mineral density, lean mass and fat mass, while structured and specific questionnaires were used to assess the habitual physical activity, food frequency and fracture risk. Habitual activity energy expenditure was also measured using an accelerometer with a combined heart rate monitor. The third study aimed to examine the association of serum 25 hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentration, respectively, with the metabolic syndrome while controlling for adiposity in black women in the North West Province, South Africa. This third study is also cross-sectional in design and it included 209 HIV-negative urban women. Dual X-ray absorptiometry was used to assess adiposity, while habitual physical activity was accessed with questionnaire and habitual activity energy expenditure was also measured using an accelerometer with a combined heart rate monitor. Results Study 1: Over a 5-year period, body mass index (BMI) and waist circumference increased in both genders, but the change was significant for BMI (P<0.01) and waist circumference (P<0.001) in women only, indicating an increase in adiposity over time. Urban residency positively predicted changes in waist circumference in men (p < 0.05) and women (p < 0.001) as well as change in triceps skinfold thickness of men (p < 0.05). Being married positively predicted changes in BMI (p < 0.001) and waist circumference (p < 0.001) in men, while age negatively predicted changes in triceps skinfold thickness in women (p < 0.001). Study 2: Fat mass and lean mass were significantly positively associated with bone mineral density (BMD) and fracture risk when adjusted for potential confounders. However, lean mass and not fat mass remained significantly associated with femoral neck BMD (β = 0.49, p <0.001), spine BMD (β = 0.48, p< 0.0001) and hip BMD (β = 0.59, p< 0.0001). Lean mass was also negatively associated with fracture risk (β = -0.19 p =0.04) when both lean and fat mass were in the same model. Study 3: After adjusting for age, body fat, habitual physical activity, tobacco use and season, neither 25(OH)D nor PTH concentrations showed significant associations with having the metabolic syndrome. However, when body fat was replaced with waist circumference there was a weak positive association between 25(OH)D concentration and the metabolic syndrome. No significant association was found between PTH:25(OH)D ratio and the metabolic syndrome. Conclusion This thesis has highlighted that the prevalence of obesity among black South Africans is high particularly among women and urbanization played a significant role in the increasing adiposity of black South Africans in the North West province. Lean mass had a stronger association with bone health in comparison to fat mass in urban black South African women. Low 25(OH)D concentration was not associated with the metabolic syndrome while there was no significant association between PTH and the metabolic syndrome in our black South African women. / PhD (Dietetics), North-West University, Potchefstroom Campus, 2015

Background In South Africa, as in many other developing countries, obesity has become a major health problem causing an increase in the incidence and prevalence of various non-communicable diseases. Research has shown that excess adiposity is associated with low vitamin D status and detrimental to bone health. Low vitamin D status has been linked to various non-communicable diseases which includes osteoporosis, and also the metabolic syndrome. Information is scarce on the role of lean mass and fat mass on bone health in the black South African population. There is also a shortage of data on the association between vitamin D status and the metabolic syndrome in the South African population. Aim The main aim of this study was to examine factors (vitamin D status, socio-economic status [SES] and lifestyle risk factors) associated with body composition, including bone health, as well as predictors of change in body composition in African adults in the North West Province of South Africa. Methods The first study that forms part of this thesis was a longitudinal study aimed at examining the effects of urbanization, socio-economic status and lifestyle factors on changes in body composition over 5 years in rural and urban black South African adults. A total of 1058 men and women above age 30 years from the Prospective Urban Rural Epidemiology study were included in this study. The second study to form part of this thesis aimed to examine the association between body composition and bone health in urban black South African women. Structured questionnaires were used to collect socio-demographic and lifestyle information including medication and tobacco use. This second study is cross-sectional in design and it included 189 postmenopausal women aged > 43 years old. Dual X-ray absorptiometry was used to assess bone mineral density, lean mass and fat mass, while structured and specific questionnaires were used to assess the habitual physical activity, food frequency and fracture risk. Habitual activity energy expenditure was also measured using an accelerometer with a combined heart rate monitor. The third study aimed to examine the association of serum 25 hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) concentration, respectively, with the metabolic syndrome while controlling for adiposity in black women in the North West Province, South Africa. This third study is also cross-sectional in design and it included 209 HIV-negative urban women. Dual X-ray absorptiometry was used to assess adiposity, while habitual physical activity was accessed with questionnaire and habitual activity energy expenditure was also measured using an accelerometer with a combined heart rate monitor. Results Study 1: Over a 5-year period, body mass index (BMI) and waist circumference increased in both genders, but the change was significant for BMI (P<0.01) and waist circumference (P<0.001) in women only, indicating an increase in adiposity over time. Urban residency positively predicted changes in waist circumference in men (p < 0.05) and women (p < 0.001) as well as change in triceps skinfold thickness of men (p < 0.05). Being married positively predicted changes in BMI (p < 0.001) and waist circumference (p < 0.001) in men, while age negatively predicted changes in triceps skinfold thickness in women (p < 0.001). Study 2: Fat mass and lean mass were significantly positively associated with bone mineral density (BMD) and fracture risk when adjusted for potential confounders. However, lean mass and not fat mass remained significantly associated with femoral neck BMD (β = 0.49, p <0.001), spine BMD (β = 0.48, p< 0.0001) and hip BMD (β = 0.59, p< 0.0001). Lean mass was also negatively associated with fracture risk (β = -0.19 p =0.04) when both lean and fat mass were in the same model. Study 3: After adjusting for age, body fat, habitual physical activity, tobacco use and season, neither 25(OH)D nor PTH concentrations showed significant associations with having the metabolic syndrome. However, when body fat was replaced with waist circumference there was a weak positive association between 25(OH)D concentration and the metabolic syndrome. No significant association was found between PTH:25(OH)D ratio and the metabolic syndrome. Conclusion This thesis has highlighted that the prevalence of obesity among black South Africans is high particularly among women and urbanization played a significant role in the increasing adiposity of black South Africans in the North West province. Lean mass had a stronger association with bone health in comparison to fat mass in urban black South African women. Low 25(OH)D concentration was not associated with the metabolic syndrome while there was no significant association between PTH and the metabolic syndrome in our black South African women. / PhD (Dietetics), North-West University, Potchefstroom Campus, 2015

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Made available in DSpace on 2015-07-22T20:49:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-24 / INTRODUÇÃO: Osteoporose Pseudoglioma (OPPG) é uma doença rara, caracterizada por osteoporose grave de início juvenil, associada a múltiplas fraturas e anormalidades oculares. É causada por uma mutação inativadora no gene da “low–density lipoprotein receptor-related protein 5” (LRP5), que está envolvido na formação óssea. O papel inicialmente proposto para o LRP5 seria sua participação na formação de um complexo receptor, juntamente com as proteínas Frizzled e Wnt na membrana dos osteoblastos, que, quando ativados, promoveriam a estabilização da beta-catenina no citoplasma destas células e induziram a formação óssea. A teriparatida, por sua vez, é um medicamento anabólico que, portanto, atua sobre a formação óssea. Seu mecanismo de ação, entretanto, ainda não está completamente esclarecido. Em camundongos com mutação inativadora do LRP5 -/- o tratamento com teriparatida induziu a um incremento da BMD, semelhante ao obtido em camundongos (LRP5 +/+), sugerindo que o efeito anabólico do PTH não utilize a via de sinalização do LRP5. Esta constatação nos incentivou a tratar com teriparatida um de nossos pacientes portador de OPPG. Ao longo deste tratamento, entretanto, uma nova teoria sobre o papel do LRP5 surgiu, associando-o à produção de serotonina intestinal. OBJETIVOS: Avaliar eficácia terapêutica da teriparatida em um paciente adulto jovem com OPPG sobre DMO e marcadores de remodelação óssea, além de dosar serotonina sérica neste paciente, em seu irmão também afetado e em controles saudáveis. PACIENTE E MÉTODOS: Paciente masculino, 19 anos com amaurose congênita e fraturas não traumáticas desde a infância. Após 3 anos de infusões periódicas de pamidronato com resposta insatisfatória, foi iniciado a teriparatida 20 mcg/dia por via subcutânea uma vez ao dia, durante 24 meses. Amostras sanguíneas e urinárias foram coletadas em jejum pela manhã nos tempos basal e a cada 3 meses até o final do tratamento. Foram determinadas a relação do cálcio/creatinina em amostra isolada de urina e as dosagens séricas de Telopeptideo Carboxiterminal do colágeno Tipo I (CTX), Peptídeo Aminoterminal do Procolágeno Tipo I (P1NP), cálcio total e ionizado, fósforo, ácido úrico, hemograma, função hepática e renal. Densitometria óssea foi realizada por Dual energy X-ray absorptiometry (DXA) a cada 12 meses. Serotonina sérica foi dosado por ELISA (kit Fitzgerald Cat# 55R- RE59121) em um único momento, logo após o término do tratamento. RESULTADOS: Os parâmetros sanguíneos e urinários estavam normais no basal e durante o tratamento. Com relação aos marcadores bioquímicos do metabolismo ósseo, notamos aumento inicial nos valores do CTX, atingindo pico no terceiro mês. O P1NP começou a aumentar no sexto mês, com pico tardio no nono mês. Apesar deste padrão não usual de resposta dos marcadores, houve aumento de 9,7% na densidade mineral óssea (DMO) em coluna lombar comparado ao basal e de 10,2% em fêmur total. As concentrações de serotonina foram duas vezes e meia maior no paciente, comparado aos valores obtidos em indivíduos normais. CONCLUSÃO: Em um paciente com OPPG previamente tratado com pamidronato, teriparatida mostrou-se segura e capaz de induzir aumento substancial da DMO de coluna lombar e fêmur proximal. Os valores elevados de serotonina plasmática concordam com os relatos descritos na literatura em outros pacientes com OPPG, mas seu papel no controle da formação óssea ainda precisa ser melhor estabelecido. / INTRODUCTION: Osteoporosis Pseudoglioma (OPPG) is characterized by severe juvenile-onset osteoporosis and ocular abnormalities. It is caused by one of several inactivating mutations in LRP5, a gene importantly involved in bone formation. OBJECTIVE: The objective of this study was to evaluate the efficacy of teriparatide in a young man with OPPG. PATIENT AND METHOD: The subject of this case report is a 19-year-old man with congenital blindness and low trauma fractures due to OPPG. A 2-year course of teriparatide, 20 mcg/day, was initiated after a 6-year course of intravenous pamidronate infusions, the latter 3 years of which had minimal effects on bone mineral density (BMD). Measurements in serum were made of C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP), total and ionized calcium, phosphate, uric acid, complete blood count, renal and liver function tests. Urinary calcium/creatinine ratio was determined. BMD was measured by DXA yearly. RESULTS: BMD increased by 9.7% in lumbar BMD and 10.2% in right femur hip. CTX rose early, peaking in month 3, followed by an increase in P1NP, peaking in month 9. Both indices returned to baseline by month 24. The increase in CTX followed by P1NP is an unusual time course when teriparatide is used to treat osteoporosis but may be typical of low bone turnover states. There were no adverse events. CONCLUSION: In a patient with OPPG, teriparatide markedly increased BMD in the lumbar spine and femur hip. / TEDE / BV UNIFESP: Teses e dissertações

Cette thèse de mathématiques appliquées en physiologie rénale a pour thème principal l'étude de l'homéostasie du calcium à travers le développement d'un modèle mathématique à l'échelle de l'organisme. Nous cherchons à répondre à certaines questions soulevées par les néphrologues dans le cas de pathologies impliquant la formation de calculs rénaux ou de calcifications. Nous examinons notamment les cas de l'hypercalciurie observée durant l'hyperparathyroïdie primaire dont les causes ne sont pas élucidées ainsi que les mécanismes de complexation du calcium et phosphate et notamment les conséquences d'une infusion intraveineuse de phosphate sur l'homéostasie du calcium. Notre modèle est composé d'équations différentielles décrivant la dynamique du calcium dans les compartiments impliqué dans son métabolisme (intestin, os, reins) ainsi que les mécanismes de régulation par l'hormone parathyroïdienne (PTH), la vitamine D3 et le récepteur sensible au calcium (CaSR). Ce modèle est par ailleurs couplé à un modèle de l'homéostasie du phosphate. Les résultats de ce modèle suggèrent que la présence ou non d'une hypercalciurie lors de l'hyperparathyroïdie primaire peut être expliquée par des mécanismes antagonistes dans la branche ascendante large de Henle, avec d'un côté le CaSR inhibant la réabsorption de calcium et de l'autre la PTH diminuant l'excrétion de calcium. Nous concluons que l'infusion intraveineuse de phosphate induit une hypocalcémie majeure, due principalement à la précipitation du calcium et du phosphate dans le plasma et dans l'os. En outre, cette étude suggère un retard dans l'activation de la synthèse de PTH par le phosphate. / This thesis of applied mathematics in renal physiology focuses on the study of calcium homeostasis, through the development of a mathematical model at the organism scale. This model is built based upon recent experimental studies as well as previous models in the field. We aim to answer several questions raised by nephrologists regarding diseases involving calcium stone formation or calcifications. In particular, we are interested in the origins of the hypercalciuria observed during primary hyperparathyroidism, the causes of which remain to be elucidated, the effects of bone resorption inhibition by bisphosphonates on calcium metabolism, as well as the consequences of an intravenous infusion of phosphate on calcium homeostasis. Our model is composed of differential equations describing the dynamics of calcium in the compartments involved in its metabolism (intestine, bone and kidneys), as well as complex feedback mechanisms by parathyroid hormone (PTH), vitamin D3 and the calcium sensing receptor (CaSR). Besides, this model is coupled to a phosphate homeostasis model. This model suggests that the variable presence of hypercalciuria during primary hyperparathyroidism can be explained by counteracting mechanisms in the thick ascending limb of Henle, involving on one hand the calcium sensing receptor, which inhibits calcium reabsorption, and on the other hand PTH which decreases calcium excretion. We conclude that the intravenous infusion of phosphate triggers a major hypocalcemia, mainly due to the precipitation of calcium and phosphate in both bone and plasma. Moreover, this study suggests a delay in the activation of PTH synthesis by phosphate

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