Browsing by Subject "parathyroid hormone"

Now showing 1 - 7 of 7
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    Adverse mandibular bone effects associated with kidney disease are only partially corrected with bisphosphonate and/or calcium treatment
    (Published article can be found at: http://www.karger.com/Article/FullText/356335 doi: 10.1159/000356335, 2013-10) Allen, Matthew R.; Chen, Neal X.; Gattone II, Vincent H.; Moe, Sharon M.
    Background/Aims: Patients with chronic kidney disease (CKD) have 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, 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 cementenamel 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 significantly higher PTH compared to normal animals yet similar levels of C-reactive protein. Zoledronate-treatment normalized BV/TV over the first 5 weeks but this benefit was lost by 10 weeks. Calcium treatment, alone or in combination with zoledronate, was effective in normalizing BV/TV at both time points. Neither zoledronate nor calcium was able to correct the higher CEJ-AC caused by CKD. Calcium, but not zoledronate, significantly reduced serum parathyroid hormone (PTH) while neither treatment affected C-reactive protein. Conclusions: 1) this progressive animal model of chronic kidney disease shows a clear mandibular skeletal phenotype consistent with periodontitis, 2) the periodontitis is not associated with systemic inflammation as measured by C-reactive protein, and 3) reducing PTH has positive effects on the mandible phenotype.
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    A clinical pathway for the postoperative management of hypocalcemia after pediatric thyroidectomy reduces blood draws
    (Elsevier, 2018-02) Patel, Neha A.; Bly, Randall A.; Adams, Seth; Carlin, Kristen; Parikh, Sanjay R.; Dahl, John P.; Manning, Scott; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Objectives Postoperative calcium management is challenging following pediatric thyroidectomy given potential limitations in self-reporting symptoms and compliance with phlebotomy. A protocol was created at our tertiary children's institution utilizing intraoperative parathyroid hormone (PTH) levels to guide electrolyte management during hospitalization. The objective of this study was to determine the effect of a new thyroidectomy postoperative management protocol on two primary outcomes: (1) the number of postoperative calcium blood draws and (2) the length of hospital stay. Study design Institutional review board approved retrospective study (2010–2016). Methods Consecutive pediatric total thyroidectomy and completion thyroidectomy ± neck dissection cases from 1/1/2010 through 8/5/2016 at a single tertiary children's institution were retrospectively reviewed before and after initiation of a new management protocol. All cases after 2/1/2014 comprised the experimental group (post-protocol implementation). The pre-protocol control group consisted of cases prior to 2/1/2014. Multivariable linear and Poisson regression models were used to compare the control and experimental groups for outcome measure of number of calcium lab draws and hospital length of stay. Results 53 patients were included (n = 23, control group; n = 30 experimental group). The median age was 15 years. 41 patients (77.4%) were female. Postoperative calcium draws decreased from a mean of 5.2 to 3.6 per day post-protocol implementation (Rate Ratio = 0.70, p < .001), adjusting for covariates. The mean number of total inpatient calcium draws before protocol initiation was 13.3 (±13.20) compared to 7.2 (±4.25) in the post-protocol implementation group. Length of stay was 2.1 days in the control group and 1.8 days post-protocol implementation (p = .29). Patients who underwent concurrent neck dissection had a longer mean length of stay of 2.32 days compared to 1.66 days in those patients who did not undergo a neck dissection (p = .02). Hypocalcemia was also associated with a longer mean length of stay of 2.41 days compared to 1.60 days in patients who did not develop hypocalcemia (p < .01). Conclusions The number of calcium blood draws was significantly reduced after introduction of a standardized protocol based on intraoperative PTH levels. The hospital length of stay did not change. Adoption of a standardized postoperative protocol based on intraoperative PTH levels may reduce the number of blood draws in children undergoing thyroidectomy.
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    Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality
    (APS, 2019) Shao, Yu; Wichern, Emily; Childress, Paul J.; Adaway, Michele; Misra, Jagannath; Klunk, Angela; Burr, David B.; Wek, Ronald C.; Mosley, Amber L.; Liu, Yunlong; Robling, Alexander G.; Brustovetsky, Nickolay; Hamilton, James; Jacobs, Kylie; Vashishth, Deepak; Stayrook, Keith R.; Allen, Matthew R.; Wallace, Joseph M.; Bidwell, Joseph P.; Anatomy and Cell Biology, IU School of Medicine
    A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.
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    Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents
    (Wolters Kluwer, 2020-06-01) Margossian, Renee; Williams, Paige L.; Yu, Wendy; Jacobson, Denise L.; Geffner, Mitchell E.; DiMeglio, Linda A.; Van Dyke, Russell B.; Spector, Stephen A.; Schuster, Gertrud U.; Stephensen, Charles B.; Miller, Tracie L.; Lipshultz, Steven E.; Study (PHACS) for the Pediatric HIV/AIDS Cohort; Pediatrics, School of Medicine
    Background: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. Setting: Adolescent Master Protocol (AMP) is a Pediatric HIV/AIDS Cohort Study (PHACS) network study conducted across 14 United States sites. Methods: Among perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youth enrolled in AMP, we evaluated associations of vitamin D (measured as 25-hydroxyvitamin D [25OHD]), parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function and concentrations of NT-proBNP, a biomarker of cardiac damage. Results: Among 485 participants (305 PHIV, 180 PHEU) with echocardiograms and bone mineralization measures, low 25OHD (< 20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (> 65 pg/mL) was identified more often among PHIV than PHEU participants (9% vs 3%, p=0.02). After adjusting for HIV status and demographic covariates, both low 25OHD and elevated PTH were associated with lower mean LV mass z-scores, while elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness both overall and among PHIV participants. Conclusion: In this cohort of PHIV and PHEU youth, we observed associations of 25OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.
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    Parathyroid Hormone Enhances Mechanically Induced Bone Formation, Possibly Involving L-Type Voltage- Sensitive Calcium Channels
    (2003-04) Li, Jiliang; Duncan, Randall L; Burr, David B.; Gattone, Vincent H; Turner, Charles H
    PTH and mechanical loading might act synergistically on bone formation. We tested the in vivo effect of the L-type voltage-sensitive calcium channel (VSCC) blocker, verapamil, on bone formation induced by human PTH-(1–34) (PTH) injection with or without mechanical loading. Adult rats were divided into eight groups: vehicle, verapamil, PTH, or verapamil plus PTH with or without mechanical loading. Verapamil (100 mg/kg) was given orally 90 min before loading. PTH (80 μg/kg) was injected sc 30 min before loading. Loading applied to tibia and ulna for 3 min significantly increased the bone formation rate on both the endocortical surface of tibia and the periosteal surface of ulna (P < 0.0001). Treatment with PTH enhanced load-induced bone formation by 53% and 76% (P < 0.001) on the endocortical and periosteal surfaces, respectively. Treatment with verapamil suppressed load-induced bone formation rate by 77% and 59% (P < 0.01). Furthermore, verapamil suppressed bone formation in rats subjected to PTH plus loading by 74% and 68% (P < 0.0001) at the tibia and ulna, respectively. In the groups without loading, neither verapamil nor PTH treatment significantly changed any bone formation parameter. This study indicates that L-type VSCCs mediate load-induced bone formation in vivo. Furthermore, PTH enhances load-induced bone adaptation through involvement of L-type VSCCs.
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    Surface-specific bone formation effects of osteoporosis pharmacological treatments
    (2008-08) Allen, Matthew R.
    Current anti-osteoporotic pharmacological treatments reduce fracture risk in part by altering bone remodeling/modeling. These effects can manifest on any or all of the bone envelopes—periosteal, intracortical, and trabecular/endocortical—each of which has unique effects on the biomechanical properties of bone. The purpose of this review is to provide an overview of how the most common FDA-approved anti-osteoporosis agents [bisphosphonates, estrogen/hormone replacement therapy, selective estrogen receptor modulators (SERMs), and parathyroid hormone (PTH)] affect tissue-level remodeling/modeling on each of the bone surfaces. Iliac crest biopsy data, the only means of assessing surface-specific bone formation in humans, exist for all of these agents although they predominately focus on trabecular/endocortical surfaces. Data from pre-clinical animal models provide an essential complement to human studies, particuarily for changes on periosteal surfaces and within the intracortical envelope. Although all of the anti-catabolic agents (estrogen replacement therapy, SERMs, bisphosphonates) exert positive effects on the various bone surfaces, the bisphosphonates produce the unique biomechanical combination of allowing normal periosteal expansion while limiting remodeling-induced bone loss on intracortical and trabecular/endocortical surfaces. PTH, the only FDA-approved anabolic agent, exerts biomechanically favorable alterations though enhanced trabecular/endocortical surface activity while also stimulating periosteal expansion. Through understanding how current and future anti-osteoporotic agents influence surface-specific bone activity we will move one step closer to developing agents that could potentially target a particular bone surface.
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    Wnt Signaling in Zebrafish Fin Regeneration: Chemical Biology Using GSK3b Inhibitors
    (Office of the Vice Chancellor for Research, 2013-04-05) Curtis, Courtney; Sarmah, Swapnalee; Collins, Kayla; Chu, Shaoyou; Sato, Mas; Sanchez-Felix, Manuel; Marrs, James A.
    Bone growth can be impaired due to disease, such as osteoporosis, and Wnt signaling pathways regulate bone growth. The parathyroid hormone (PTH) is therapeutic for anabolic bone growth (bone building), which activates Wnt signaling, leading to bone growth. GSK3b (glycogen synthetase kinase 3 beta) protein inhibitors activate Wnt signaling, including in bone growth models. Our study utilized a zebrafish model system to study Wnt activated fin regeneration and bone growth. Wnt signaling is the first genetically identified step in fin regeneration, and bony rays are the main differentiated cell type in fins. Thus, zebrafish fin regeneration may be a useful model to study Wnt signaling mediated bone growth. Fin regeneration experiments were conducted using various concentrations of GSK3b inhibitor compound for different treatment periods and regenerative outgrowth was measured at 4 and 7 days post amputation. Experiments revealed continuous low concentration (5-6 nM) treatment to be most effective at increasing regeneration. Higher concentrations inhibited fin growth, perhaps by excessive stimulation of differentiation programs. In situ hybridization experiments were performed to examine effects of Gsk3b inhibitor on Wnt responsive gene expression. Initial experiments show temporal and spatial changes on individual gene markers following GSK3b inhibitor treatment. Additionally, confocal microscopy and immunofluorescence labeling data indicated that the Wnt signaling intracellular signal transducer, betacatenin, accumulates throughout Gsk3b inhibitor treated tissues. Finally, experiments are underway to quantify phosphohistone-3 staining in regenerating tissue to measure effects of Gsk3b inhibitor on cell proliferation. Together, these data indicate that bone growth in zebrafish fin regeneration is improved by activating Wnt signaling. Zebrafish Wnt signaling experiments provide good model to study bone growth and bone repair mechanisms, and may provide an efficient drug discovery platform.