Browsing by Subject "Parathyroid hormone"
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Item Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment(Karger, 2013) Allen, Matthew R.; Chen, Neal X.; Gattone II, Vincent H.; Moe, Sharon M.; Anatomy & Cell Biology, School of MedicineBACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have a high prevalence of periodontal disease that may predispose to tooth loss and inflammation. The goal of this study was to test the hypotheses that a genetic rat model of progressive CKD would exhibit altered oral bone properties and that treatment with either bisphosphonates or calcium could attenuate these adverse changes. METHODS: At 25 weeks of age, rats were treated with zoledronate (ZOL), calcium gluconate, or their combination for 5 or 10 weeks. Mandible bone properties were assessed using micro-computed tomography to determine bone volume (BV/TV) and cementum-enamel junction to alveolar crest distance (CEJ-AC). RESULTS: Untreated CKD animals had significantly lower BV/TV at both 30 (-5%) and 35 (-14%) weeks of age and higher CEJ-AC (+27 and 29%) compared to normal animals. CKD animals had a significantly higher parathyroid hormone (PTH) compared to normal animals, yet similar levels of C-reactive protein (CRP). ZOL treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with ZOL, was effective in normalizing BV/TV at both time points. Neither ZOL nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not ZOL, significantly reduced serum PTH, while neither treatment affected CRP. CONCLUSIONS: (i) This progressive animal model of CKD shows a clear mandibular skeletal phenotype consistent with periodontitis, (ii) the periodontitis is not associated with systemic inflammation as measured by CRP, and (iii) reducing PTH has positive effects on the mandible phenotype.Item Associations of Low Vitamin D and Elevated Parathyroid Hormone Concentrations With Bone Mineral Density in Perinatally HIV-Infected Children(Wolters Kluwer, 2017-09-01) Jacobson, Denise L.; Stephensen, Charles B.; Miller, Tracie L.; Patel, Kunjal; Chen, Janet S.; Van Dyke, Russell B.; Mirza, Ayesha; Schuster, Gertrud U.; Hazra, Rohan; Ellis, Angela; Brummel, Sean S.; Geffner, Mitchell E.; Silio, Margarita; Spector, Stephen A.; DiMeglio, Linda A.; Pediatrics, School of MedicineBACKGROUND: Perinatally HIV-infected (PHIV) children have, on average, lower bone mineral density (BMD) than perinatally HIV-exposed uninfected (PHEU) and healthy children. Low 25-hydroxy vitamin D [25(OH)D] and elevated parathyroid hormone (PTH) concentrations may lead to suboptimal bone accrual. METHODS: PHIV and PHEU children in the Pediatric HIV/AIDS Cohort Study had total body (TB) and lumbar spine (LS) BMD and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry; BMD z-scores (BMDz) were calculated for age and sex. Low 25(OH)D was defined as ≤20 ng/mL and high PTH as >65 pg/mL. We fit linear regression models to estimate the average adjusted differences in BMD/BMC by 25(OH)D and PTH status and log binomial models to determine adjusted prevalence ratios of low 25(OH)D and high PTH in PHIV relative to PHEU children. RESULTS: PHIV children (n = 412) were older (13.0 vs. 10.8 years) and more often black (76% vs. 64%) than PHEU (n = 207). Among PHIV, children with low 25(OH)D had lower TB-BMDz [SD, -0.38; 95% confidence interval (CI), -0.60 to -0.16] and TB-BMC (SD, -59.1 g; 95% CI, -108.3 to -9.8); high PTH accompanied by low 25(OH)D was associated with lower TB-BMDz. Among PHEU, children with low 25(OH)D had lower TB-BMDz (SD, -0.34; 95% CI, -0.64 to -0.03). Prevalence of low 25(OH)D was similar by HIV status (adjusted prevalence ratio, 1.00; 95% CI, 0.81 to 1.24). High PTH was 3.17 (95% CI, 1.25 to 8.06) times more likely in PHIV children. CONCLUSIONS: PHIV and PHEU children with low 25(OH)D may have lower BMD. Vitamin D supplementation trials during critical periods of bone accrual are needed.Item Black bear parathyroid hormone has greater anabolic effects on trabecular bone in dystrophin-deficient mice than in wild type mice(Elsevier, 2012) Gray, Sarah K.; McGee-Lawrence, Meghan E.; Sanders, Jennifer L.; Condon, Keith W.; Tsai, Chung-Jui; Donahue, Seth W.; Anatomy, Cell Biology and Physiology, School of MedicineDuchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease that has deleterious consequences in muscle and bone, leading to decreased mobility, progressive osteoporosis, and premature death. Patients with DMD experience a higher-than-average fracture rate, particularly in the proximal and distal femur and proximal tibia. The dystrophin-deficient mdx mouse is a model of DMD that demonstrates muscle degeneration and fibrosis and osteoporosis. Parathyroid hormone, an effective anabolic agent for post-menopausal and glucocorticoid-induced osteoporosis, has not been explored for DMD. Black bear parathyroid hormone (bbPTH) has been implicated in the maintenance of bone properties during extended periods of disuse (hibernation). We cloned bbPTH and found 9 amino acid residue differences from human PTH. Apoptosis was mitigated and cAMP was activated by bbPTH in osteoblast cultures. We administered 28nmol/kg of bbPTH 1-84 to 4-week old male mdx and wild type mice via daily (5×/week) subcutaneous injection for 6 weeks. Vehicle-treated mdx mice had 44% lower trabecular bone volume fraction than wild type mice. No changes were found in femoral cortical bone geometry or mechanical properties with bbPTH treatment in wild type mice, and only medio-lateral moment of inertia changed with bbPTH treatment in mdx femurs. However, μCT analyses of the trabecular regions of the distal femur and proximal tibia showed marked increases in bone volume fraction with bbPTH treatment, with a greater anabolic response (7-fold increase) in mdx mice than wild type mice (2-fold increase). Trabecular number increased in mdx long bone, but not wild type bone. Additionally, greater osteoblast area and decreased osteoclast area were observed with bbPTH treatment in mdx mice. The heightened response to PTH in mdx bone compared to wild type suggests a link between dystrophin deficiency, altered calcium signaling, and bone. These findings support further investigation of PTH as an anabolic treatment for DMD-induced osteoporosis.Item Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis(American Society of Nephrology, 2017-07-07) Moe, Sharon M.; Wetherill, Leah; Decker, Brian Scott; Lai, Dongbing; Abdalla, Safa; Long, Jin; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.; Medicine, School of MedicineBACKGROUND AND OBJECTIVES: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS: There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS: These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.Item Control of Bone Anabolism in Response to Mechanical Loading and PTH by Distinct Mechanisms Downstream of the PTH Receptor(Wiley, 2017-03) Delgado-Calle, Jesus; Tu, Xiaolin; Pacheco-Costa, Rafael; McAndrews, Kevin; Edwards, Rachel; Pellegrini, Gretel G.; Kuhlenschmidt, Kali; Olivos, Naomie; Robling, Alexander; Peacock, Munro; Plotkin, Lilian I.; Bellido, Teresita; Anatomy, Cell Biology and Physiology, School of MedicineOsteocytes integrate the responses of bone to mechanical and hormonal stimuli by poorly understood mechanisms. We report here that mice with conditional deletion of the parathyroid hormone (PTH) receptor 1 (Pth1r) in dentin matrix protein 1 (DMP1)-8kb-expressing cells (cKO) exhibit a modest decrease in bone resorption leading to a mild increase in cancellous bone without changes in cortical bone. However, bone resorption in response to endogenous chronic elevation of PTH in growing or adult cKO mice induced by a low calcium diet remained intact, because the increased bone remodeling and bone loss was indistinguishable from that exhibited by control littermates. In contrast, the bone gain and increased bone formation in cancellous and cortical bone induced by daily injections of PTH and the periosteal bone apposition induced by axial ulna loading were markedly reduced in cKO mice compared to controls. Remarkably, however, wild-type (WT) control littermates and transgenic mice overexpressing SOST injected daily with PTH exhibit similar activation of Wnt/β-catenin signaling, increased bone formation, and cancellous and cortical bone gain. Taken together, these findings demonstrate that Pth1r in DMP1-8kb-expressing cells is required to maintain basal levels of bone resorption but is dispensable for the catabolic action of chronic PTH elevation; and it is essential for the anabolic actions of daily PTH injections and mechanical loading. However, downregulation of Sost/sclerostin, previously shown to be required for bone anabolism induced by mechanical loading, is not required for PTH-induced bone gain, showing that other mechanisms downstream of the Pth1r in DMP1-8kb-expressing cells are responsible for the hormonal effect.Item Differential regulation of myeloid leukemias by the bone marrow microenvironment(Springer Nature, 2013) Krause, Daniela S.; Fulzele, Keertik; Catic, Andre; Sun, Chia Chi; Dombkowski, David; Hurley, Michael P.; Lezeau, Sanon; Attar, Eyal; Wu, Joy Y.; Lin, Herbert Y.; Divieti-Pajevic, Paola; Hasserjian, Robert P.; Schipani, Ernestina; Van Etten, Richard A.; Scadden, David T.; Medicine, School of MedicineLike their normal hematopoietic stem cell counterparts, leukemia stem cells (LSCs) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM) and may be the cause of relapse following chemotherapy. Targeting the niche is a new strategy to eliminate persistent and drug-resistant LSCs. CD44 (refs. 3,4) and interleukin-6 (ref. 5) have been implicated previously in the LSC niche. Transforming growth factor-β1 (TGF-β1) is released during bone remodeling and plays a part in maintenance of CML LSCs, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor attenuates BCR-ABL1 oncogene-induced CML-like myeloproliferative neoplasia (MPN) but enhances MLL-AF9 oncogene-induced AML in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSCs. PTH treatment caused a 15-fold decrease in LSCs in wild-type mice with CML-like MPN and reduced engraftment of immune-deficient mice with primary human CML cells. These results demonstrate that LSC niches in CML and AML are distinct and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSCs, a prerequisite for the cure of CML.Item Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD(SpringerLink, 2020-04) Metzger, Corinne E.; Swallow, Elizabeth A.; Allen, Matthew R.; Anatomy and Cell Biology, School of MedicineChronic kidney disease (CKD) leads to significant bone loss primarily through the development of cortical porosity. In both patients and animal models of CKD, sustained elevations in serum parathyroid hormone (PTH) are associated with cortical porosity. In this study, we aimed to track the progression of cortical porosity and increased PTH utilizing the adenine-induced CKD model. Young female mice (8 weeks) were given 0.2% adenine to induce CKD. Tissues were collected from groups of adenine and age-matched control mice after 2, 6, and 10 weeks. Serum blood urea nitrogen was elevated at all time points in adenine mice, but serum PTH was only statistically elevated at the 10-week time point. Cortical porosity was sevenfold higher in 6-week adenine mice compared to age-matched controls and 14-fold higher in 10-week adenine mice vs. controls. Additionally, osteocyte receptor activator of nuclear factor κB ligand (RANKL) was elevated in adenine-fed mice, while annexin V, an early marker of cellular apoptosis, was mildly decreased in osteocytes in adenine-fed mice. Based on these results, we hypothesize high serum PTH signals to osteocytes prolonging their lifespan resulting in sustained RANKL which drives osteoclastic bone resorption in the cortex. In conclusion, our data show time-dependent elevations in serum PTH and cortical porosity in adenine-induced CKD mice and demonstrate changes in osteocyte RANKL and apoptosis which may contribute to the development of cortical pores.Item Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism(Oxford University Press, 2017-09-01) Shao, Yu; Hernandez-Buquer, Selene; Childress, Paul; Stayrook, Keith R.; Alvarez, Marta B.; Davis, Hannah; Plotkin, Lilian I.; He, Yongzheng; Condon, Keith W.; Burr, David B.; Warden, Stuart J.; Robling, Alexander G.; Yang, Feng-Chun; Wek, Ronald C.; Allen, Matthew R.; Bidwell, Joseph P.; Medical and Molecular Genetics, School of MedicineCombining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.Item Nmp4 restricts bone marrow osteoprogenitors and parathyroid hormone induced bone formation in healthy and estrogen depleted female mice(2014-12) Childress, Paul Jeffrey; Bidwell, Joseph P.; Pavalko, Fredrick M.; Bellido, Teresita; Robling, Alexander G.; Kacena, Melissa A.We have shown that nuclear matrix protein 4 (Nmp4) attenuates the response to intermittent parathyroid hormone (PTH) in healthy and ovariectomized (OVX) female mice using a global knockout of the Nmp4 gene. Additionally, these mice have increased bone marrow osteoprogenitors and CD8+ T-cells which support osteoblast differentiation. The animals were not protected from bone loss following OVX, but retained the hypersensitivity seen in the intact mice. Mesenchymal stem/progenitor cells (osteoprogenitors) demonstrated increased growth rate in culture and showed more robust differentiation into mineralizing bone cells. Chromosome precipitation followed by next generation sequencing and bioinformatics analysis characterized Nmp4 as a negative regulator of synthetic processes and suggested the IGF1/Akt and BMP2/Smad biochemical pathways which are likely targets for Nmp4 regulation. We have experimentally verified these pathways in immortalized bone marrow mesenchymal cells from wild type and Nmp4-KO mice. Disabling Nmp4 in estrogen replete or depleted mice confers an enhanced bone formation from intermittent parathyroid hormone.Item Oh, My Gut! New insights on the role of the gastrointestinal tract and the gut microbiome in chronic kidney disease-mineral and bone disorder(Wolters Kluwer, 2024) Mirmohammadali, Seyedeh Nooshan; Hill Gallant, Kathleen M.; Biruete, Annabel; Medicine, School of MedicinePurpose of review: The aim of this review is to highlight recent evidence on the role of the gastrointestinal tract and gut microbiome on chronic kidney disease-mineral bone disorder (CKD-MBD) outcomes, including intestinal phosphorus absorption and sensing, and the effect of gut-oriented therapies. Recent findings: Recent evidence has revealed a complex interplay among mineral metabolism and novel gut-related factors, including paracellular intestinal phosphate absorption, the gut microbiome, and the immune system, prompting a reevaluation of treatment approaches for CKD-MBD. The inhibition of NHE3 limits phosphate transport in the intestine and may lead to changes in the gut microbiome. A study in rats with CKD showed that the supplementation of the fermentable dietary inulin delayed CKD-MBD, lowering circulating phosphorus and parathyroid hormone, reducing bone remodeling and improving cortical parameters, and lowering cardiovascular calcifications. In non-CKD preclinical studies, probiotics and prebiotics improved bone formation mediated through the effect of butyrate facilitating the differentiation of T cells into Tregs, and Tregs stimulating the osteogenic Wnt10b, and butyrate was also necessary for the parathyroid hormone (PTH) bone effects. Summary: Recent findings support multiple possible roles for gut-oriented therapies in addressing CKD-MBD prevention and management that should be further explored through clinical and translational studies.