- Surgical thyroparathyroidectomy prevents progression of 5TGM1 murine multiple myeloma in vivo. [Review]
- JBJ Bone Oncol 2018; 12:19-22
- The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Sin…
The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Since a significant association between serum parathyroid hormone PTH variations, bone anabolism and myeloma progression in patients receiving proteasome inhibitors exists, this study investigated the effect of the PTH axis on murine myeloma development in vivo. C57BL6/KaLwRij myeloma-bearing mice underwent thyroparathyroidectomy (TPTX) before and after 5TGM1 cell transplantation. TPTX significantly and permanently inhibited 5TGM1 myeloma cell engraftment and prevented multiple myeloma growth and progression. These data support the hypothesis that the PTH axis is an important mediator of myeloma bone disease.
- Thymic PTH Increases After Thyroparathyroidectomy in C57BL/KaLwRij Mice. [Journal Article]
- EEndocrinology 2018 04 01; 159(4):1561-1569
- We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 s…
We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 system in the control of myeloma tumor growth. While investigating the role of PTH in the antimyeloma effect, we observed the recovery of serum PTH levels after thyroparathyroidectomy (TPTX). Although the presence of thymus-derived PTH has been reported previously, the existence or role of thymic PTH in the serum remains controversial. Here, TPTX was performed in 8- to 12-week-old C57BL/KaLwRij mice to delineate the potential source(s) for the recovery of serum PTH. Immediately after TPTX, the expected loss of measurable serum PTH was observed. Serum PTH levels recovered 3 to 4 weeks after TPTX. Thirteen endocrine organs from mice with recovered serum PTH were examined. The thymus from control mice expressed measurable and detectable Pth transcripts; however, the Pth transcript level was substantially elevated in tissue from TPTX mice. Western blot analysis of the thymus demonstrated a reproducible and distinct PTH band in thymus tissue that was significantly increased after TPTX. To directly confirm the identity of the distinct PTH band, immunoprecipitated proteins were isolated and subjected to tandem mass spectrometry. After fragmentation and direct peptide sequencing, PTH peptides PTH(1-13) and PTH(54-70), diagnostic for PTH, were identified. These data demonstrate that the murine thymus produces PTH and that after TPTX the thymus becomes the major source of serum PTH, compensating for the loss of the parathyroid glands and returning circulating PTH levels to normal.
- Altered material properties are responsible for bone fragility in rats with chronic kidney injury. [Journal Article]
- BONEBone 2015; 81:247-254
- Chronic kidney disease (CKD) is associated with an increased risk of fragility fractures, but the underlying pathophysiological mechanism remains obscure. We performed an in vivo experimental study t…
Chronic kidney disease (CKD) is associated with an increased risk of fragility fractures, but the underlying pathophysiological mechanism remains obscure. We performed an in vivo experimental study to examine the roles of uremia and abnormal mineral/parathyroid metabolism in the development of bone metabolic abnormalities in uremic rats. Male Sprague-Dawley rats were divided into four groups, comprising sham operation (high turnover bone control=HTB-Cont), 5/6-nephrectomy (high turnover bone nephrectomized=HTB-Nx), thyroparathyroidectomy (low turnover bone control=LTB-Cont), and thyroparathyroidectomy plus 5/6 nephrectomy (low turnover bone nephrectomized=LTB-Nx), and maintained for 16 weeks. Uremia was successfully created in the LTB-Nx and HTB-Nx groups, while hyperparathyroidism was only found in the HTB-Nx group. Cancellous bone histomorphometry revealed significantly higher bone turnover in the HTB-Nx group than in the LTB-Nx group. Storage modulus at 1 Hz and tan delta in cortical bone of the femur, which represent the viscoelastic mechanical properties, were significantly lower in both Nx groups than in the Cont groups regardless of bone metabolism. Pentosidine-to-matrix ratio was increased and crystallinity was decreased in both Nx groups regardless of bone turnover. Mineral-to-matrix ratio was significantly decreased in the HTB-Nx group, but increased in the LTB-Nx group. Enzymatic collagen crosslinks were decreased in the HTB-Nx group. The degree of orientation of the c-axis in carbonated hydroxyapatite (biological apatite=BAp) crystallites was decreased in both Nx groups regardless of bone metabolism. Stepwise multivariate regression revealed that pentosodine-to-matrix ratio and BAp preferential c-axis orientation were significantly associated with storage modulus and tan delta. In conclusion, bone elastic mechanical properties deteriorated regardless of bone metabolism or bone mass in rats with chronic kidney injury. Various changes in bone mineral properties were associated with CKD, including abnormal parathyroid function, impaired bone turnover, and uremia associated with the accumulation of uremic toxins, were responsible for these changes. Pentosidine-to-matrix ratio and BAp orientation at position 5 were the two meaningful determinants of elastic bone mechanical strength, and both factors were associated with the severity of uremia, but not parathyroid function or bone metabolism. These two factors may account for the increased bone fragility among CKD patients.
- Hypercalcemic crisis due to primary hyperparathyroidism occurring concomitantly with Graves' disease. [Case Reports]
- IMIntern Med 2015; 54(7):813-8
- We herein describe a case of hypercalcemic crisis in a 52-year-old Japanese woman. She suffered from thirst and fatigue for one month. Her serum calcium (a) levels were 19.0 mg/dL, and she was diagno…
We herein describe a case of hypercalcemic crisis in a 52-year-old Japanese woman. She suffered from thirst and fatigue for one month. Her serum calcium (a) levels were 19.0 mg/dL, and she was diagnosed with hypercalcemic crisis. Circulating levels of parathyroid and thyroid hormones were elevated. She was diagnosed with primary hyperparathyroidism accompanied by Graves' disease. Thyroparathyroidectomy was performed after circulating levels of Ca and thyroid hormones were normalized. Both of primary hyperparathyroidism and Graves' disease can contribute and accelerate hypercalcemia, resulting in a state of crisis. The possibility of their coexistence should therefore be taken into consideration in cases of hypercalcemia.
- Oxidative stress in patients with thyroidectomy and thyroparathyroidectomy under replacement therapy. [Journal Article]
- EEndocrine 2015; 48(1):227-32
- Several studies have demonstrated an imbalance between free radicals and the antioxidative system in individuals with thyroid dysfunction. However, oxidative stress has not been evaluated in patients…
Several studies have demonstrated an imbalance between free radicals and the antioxidative system in individuals with thyroid dysfunction. However, oxidative stress has not been evaluated in patients with thyroidectomy and thyroparathyroidectomy, who are under replacement therapy. The objective of this study was to evaluate the oxidative stress using malondialdehyde, nitric oxide, and catalase levels in patients with thyroidectomy and thyroparathyroidectomy. Nineteen patients with thyroidectomy, 20 patients with thyroparathyroidectomy, and 20 controls with no history of thyroid or parathyroid disease or surgery were included in the study. Serum malondialdehyde, nitric oxide, and catalase levels were examined. Levels of nitric oxide and malondialdehyde were elevated, and catalase levels decreased in patients with thyroidectomy and thyroparathyroidectomy compared with controls (p value for all the parameters: p<0.001). Free tetraiodothyronine was a potential predictor of malondialdehyde in the patient groups (p: 0.002). Catalase was negatively correlated with nitric oxide (p<0.01) and malondialdehyde (p<0.01). The results of the current study demonstrated that oxidative stress increased in patients with thyroidectomy and thyroparathyroidectomy despite the application of replacement therapies.
- Hepatectomy-related hypophosphatemia: a novel phosphaturic factor in the liver-kidney axis. [Journal Article]
- JAJ Am Soc Nephrol 2014; 25(4):761-72
- Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of…
Marked hypophosphatemia is common after major hepatic resection, but the pathophysiologic mechanism remains unknown. We used a partial hepatectomy (PH) rat model to investigate the molecular basis of hypophosphatemia. PH rats exhibited hypophosphatemia and hyperphosphaturia. In renal and intestinal brush-border membrane vesicles isolated from PH rats, Na(+)-dependent phosphate (Pi) uptake decreased by 50%-60%. PH rats also exhibited significantly decreased levels of renal and intestinal Na(+)-dependent Pi transporter proteins (NaPi-IIa [NaPi-4], NaPi-IIb, and NaPi-IIc). Parathyroid hormone was elevated at 6 hours after PH. Hyperphosphaturia persisted, however, even after thyroparathyroidectomy in PH rats. Moreover, DNA microarray data revealed elevated levels of nicotinamide phosphoribosyltransferase (Nampt) mRNA in the kidney after PH, and Nampt protein levels and total NAD concentration increased significantly in the proximal tubules. PH rats also exhibited markedly increased levels of the Nampt substrate, urinary nicotinamide (NAM), and NAM catabolites. In vitro analyses using opossum kidney cells revealed that NAM alone did not affect endogenous NaPi-4 levels. However, in cells overexpressing Nampt, the addition of NAM led to a marked decrease in cell surface expression of NaPi-4 that was blocked by treatment with FK866, a specific Nampt inhibitor. Furthermore, FK866-treated mice showed elevated renal Pi reabsorption and hypophosphaturia. These findings indicate that hepatectomy-induced hypophosphatemia is due to abnormal NAM metabolism, including Nampt activation in renal proximal tubular cells.
- Accumulated uremic toxins attenuate bone mechanical properties in rats with chronic kidney disease. [Journal Article]
- BONEBone 2013; 57(2):477-83
- The prevalence of hip fracture is very high among patients with chronic kidney disease (CKD); however, the reason for this is unclear. We examined the effects of accumulated uremic toxins on bone che…
The prevalence of hip fracture is very high among patients with chronic kidney disease (CKD); however, the reason for this is unclear. We examined the effects of accumulated uremic toxins on bone chemical composition and elastic mechanical properties. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx-Nx), and were administered with vehicle or AST-120 to reduce serum indoxyl sulfate (IS) levels. Bone mechanical properties, bone mineral density (BMD), cortical bone chemical composition, and histomorphometry were determined. Storage modulus was reduced in TPTx-Nx rats compared with rats that underwent TPTx alone. BMD and histomorphometric parameters did not differ between the groups. In terms of cortical bone chemical composition, the mineral/matrix ratio and carbonate substitution was increased, whereas crystallinity was decreased in TPTx-Nx rats. The enzymatic crosslink ratio and pentosidine:matrix ratio were increased in TPTx-Nx rats. AST-120 abolished the effects of TPTx-Nx and decreased the serum IS concentration. Stepwise multiple regression analysis revealed that the pentosidine:matrix and mineral:matrix ratios were independent contributors to the storage modulus. In conclusion, the accumulated uremic toxins, including IS, seem to play an important role in deteriorating bone mechanical properties by altering the chemical composition of bone. This mechanism may account for the increased prevalence of hip fracture among patients with CKD.
- Reduction of gastrointestinal motility by unilateral thyroparathyroidectomy plus subdiaphragmatic vagotomy in rats. [Journal Article]
- WJWorld J Gastroenterol 2012 Sep 07; 18(33):4570-7
- CONCLUSIONS: The results indicate that unilateral TPX plus VAX reduced the motor function of the GI tract in rats, and the reduced gut motility is likely mediated, at least in part, by inhibition of the excitatory neurotransmitter system.
- Changes in chemical composition of cortical bone associated with bone fragility in rat model with chronic kidney disease. [Journal Article]
- BONEBone 2011 Jun 01; 48(6):1260-7
- Bone fragility is a complication of chronic kidney disease (CKD). Patients on dialysis have higher risk of fracture than the general population, but the reason remains obscure. Bone strength is deter…
Bone fragility is a complication of chronic kidney disease (CKD). Patients on dialysis have higher risk of fracture than the general population, but the reason remains obscure. Bone strength is determined by bone mass and bone quality. Although factors affecting bone quality include microarchitecture, remodeling activity, mineral content, and collagen composition, it remains unclear which factor is critically important for bone strength in CKD. We conducted an in vivo study to elucidate the factors that reduce bone mechanical property in CKD. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx-Nx). Bone mechanical property, bone mineral density (BMD), and cortical bone chemical composition (all in femur) as well as histomorphometry (in tibia) were determined. The storage modulus, which is a mechanical factor, was reduced in CKD model rats compared with controls that underwent thyroparathyroidectomy alone (TPTx). There were no differences in BMD and histomorphometric parameters between groups. However, cortical bone chemical composition differed: mineral to matrix ratio and carbonate substitution increased whereas crystallinity decreased in TPTx-Nx. In addition, enzymatic crosslinks ratio and pentosidine to matrix ratio also increased. These changes were significant in TPTx-Nx rats with most impaired renal function. Stepwise multiple regression analysis identified mature to immature crosslink ratio and crystallinity as independent contributors to storage modulus. Deteriorated bone mechanical properties in CKD may be caused by changes in chemical composition of the cortical bone, and is independent of BMD or cancellous bone microarchitecture.
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- Effects of calcitonin and parathyroid hormone on the regulation of cabindin-D(9k) in the uterus, placenta, and fetal membrane of rats related to blood calcium level during late gestation. [Journal Article]
- MRMol Reprod Dev 2007; 74(9):1188-97
- Calbindin-D(9k) (CaBP-9k) gene is expressed in the uterus of pregnant rats, which is regulated by steroid hormones during estrous cycle or gestation. We hypothesized that there is a positive correlat…
Calbindin-D(9k) (CaBP-9k) gene is expressed in the uterus of pregnant rats, which is regulated by steroid hormones during estrous cycle or gestation. We hypothesized that there is a positive correlation between altered CaBP-9k expression and change in one or more of the hormones to provide a clue to the mechanism responsible for the altered calcium levels in the uterus, placenta, and fetal membrane during late gestation. Thus, in the present study, we investigated the effects of the hormones including estradiol (E2), calcitonin (CT), and parathyroid hormone (PTH) on the regulation of CaBP-9k in these tissues. There was an increase in the level of CaBP-9k in the uterus, placenta, and extra-embryonic membrane at late gestation, as blood calcium level increased. The protein level of CaBP-9k remained lower in the uterus at two-thirds of pregnancy, and then it rebounded abruptly during late pregnancy. During late gestation, E2 is postulated to be a dominant factor in the regulation of uterine CaBP-9k gene expression. Furthermore, we assumed that there is a positive correlation between altered expression of CaBP-9k and blood calcium level during pregnancy. The present study demonstrated the regulation of CaBP-9k mRNA in the uterus, placenta, and fetal membrane of rats, implying a role for CaBP-9k gene in the control of blood calcium in placenta and the calcium passing from maternal blood to fetal circulation. Taken together, these results suggest that major alterations in calcium metabolism caused by maternal thyroparathyroidectomy (TPTX), are sufficient to affect the changes in reproductive tissues during late pregnancy. In addition, an increase of blood calcium level is one of the most significant factors in the regulation of CaBP-9k at the transcriptional and/or translational levels in the reproductive tissues during late pregnancy.