1,25‐Dihydroxyvitamin D 3 ‐induced intestinal calcium transport is impaired in β ‐globin knockout thalassemic mice

American Journal of Physiology-Endocrinology and Metabolism

et al. 2016

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-Previously, ␤-thalassemia, an inherited anemic disorder with iron overload caused by loss-of-function mutation of ␤-globin gene, has been reported to induce osteopenia and impaired whole body calcium metabolism, but the pathogenesis of aberrant calcium homeostasis remains elusive. Herein, we investigated how ␤-thalassemia impaired intestinal calcium absorption and whether it could be restored by administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] or hepcidin, the latter of which was the liver-derived antagonist of intestinal iron absorption. The results showed that, in hemizygous ␤-globin knockout (BKO) mice, the duodenal calcium transport was lower than that in wild-type littermates, and severity was especially pronounced in female mice. Both active and passive duodenal calcium fluxes in BKO mice were found to be less than those in normal mice. This impaired calcium transport could be restored by 7-day 1,25(OH)2D3 treatment. The 1,25(OH)2D3-induced calcium transport was diminished by inhibitors of calcium transporters, e.g., L-type calcium channel, NCX1, and PMCA1b, as well as vesicular transport inhibitors. Interestingly, the duodenal calcium transport exhibited an inverse correlation with transepithelial iron transport, which was markedly enhanced in thalassemic mice. Thus, 3-day subcutaneous hepcidin injection and acute direct hepcidin exposure in the Ussing chamber were capable of restoring the thalassemia-associated impairment of calcium transport; however, the positive effect of hepcidin on calcium transport was completely blocked by proteasome inhibitors MG132 and bortezomib. In conclusion, both 1,25(OH)2D3 and hepcidin could be used to alleviate the ␤-thalassemia-associated impairment of calcium absorption. Therefore, our study has shed light on the development of a treatment strategy to rescue calcium dysregulation in ␤-thalassemia.

Section: Discussionmentioning

confidence: 62%

Hepcidin and 1,25(OH)₂D₃effectively restore Ca²⁺transport in β-thalassemic mice: reciprocal phenomenon of Fe²⁺and Ca²⁺absorption

Kraidith

American Journal of Physiology-Endocrinology and Metabolism

et al. 2016

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“…Indeed, ␤-thalassemia was previously found to disrupt intestinal absorption of both calcium and vitamin D (1,32,39), thereby curtailing calcium supply for bone mineralization. Suppression of intestinal calcium absorption in thalassemic mice was very severe, with 40 -50% reduction in the duodenal calcium transport rate, which was also intractable to a standard 1,25(OH) 2 D 3 supplementation (1 g·kg Ϫ1 ·day Ϫ1 sc for 3 days), a regimen known to markedly stimulate calcium absorption in wild-type mice (5). A study in homozygous ␤-thalassemia patients also confirmed the presence of fecal calcium wasting (21).…”

Section: Discussionmentioning

confidence: 70%

“…Our recent preliminary study in sexually mature male hemizygous ␤ IVSII-654 thalassemic mice showed that ␤ IVSII-654 -induced thalassemia tended to be associated with low bone mineral density (BMD) and impaired bone microstructure (30). What caused this skeletal defect in thalassemic mice was not known, but it was suggested that impaired intestinal calcium absorption could have eventually led to increased osteoclast activity and excessive bone resorption (5,30). A body of evidence also strongly suggested the presence of age-and sex-dependent regulation of calcium and bone metabolism.…”

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confidence: 99%

Bone microstructural defects and osteopenia in hemizygous β^IVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

Thongchote

American Journal of Physiology-Endocrinology and Metabolism

et al. 2015

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Thongchote K, Svasti S, Teerapornpuntakit J, Suntornsaratoon P, Krishnamra N, Charoenphandhu N. Bone microstructural defects and osteopenia in hemizygous ␤ IVSII-654 knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function. Am J Physiol Endocrinol Metab 309: E936 -E948, 2015. First published October 20, 2015 doi:10.1152/ajpendo.00329.2015.-␤-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age-and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in ␤ IVSII-654 knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a ␤ IVSII-654 knockin mouse model of human ␤-thalassemia, in which impaired splicing of ␤-globin transcript was caused by hemizygous C¡T mutation at nucleotide 654 of intron 2. Young, growing ␤ IVSII-654 mice (1 mo old) manifested shorter bone length and lower BMD than their wild-type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and ␤ IVSII-654 genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male ␤ IVSII-654 mice, particularly during a growing period (1-2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female ␤ IVSII-654 mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female ␤ IVSII-654 knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes. ␤-thalassemia; bone histomorphometry; bone mineral density; osteoporosis ABERRANT SPLICING of ␤-globin messenger ribonucleic acid (mRNA) can lead to a hereditary autosomal recessive anemia known as ␤-thalassemia, which exhibits infantile onset of microcytic anemia, ineffective erythropoiesis, iron overload with iron deposition in solid organs, and bone marrow expansion (34). In several geographical regions, such as Southeast Asia and China, aberrant ␤-globin mRNA splicing caused by hemizygous C¡T mutation at nucleotide 654 of intron 2 (i.e., ϩ/␤ ) results in thalassemia intermedia, a mild-tomoderate form of ␤-thalassemia (6,16,19). ␤-Thalassemia not only impairs intramedullary erythropoiesis but is also associated with trabecular bone defect; however, the underlying mechanisms and detailed microstructural changes are not completely understood (14).To investigate the pathogenesis of ␤-thalassemia-associated sequelae, a transgenic mouse model subjected to human ␤ sequence knockin was used in the present study. Our recent preliminary study in sexually...

“…Interestingly, the hemizygous ␤-globin knockout thalassemic (BKO) mice also exhibited a marked decrease in 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]-dependent calcium absorption in the small intestine, which might, in turn, diminish matrix mineralization and bone formation (7). Moreover, the thalassemia-induced intestinal malabsorption of vitamin D and disturbances of calciotropic hormones, such as low serum levels of parathyroid hormone (PTH) and vitamin D, could further aggravate the impairment of bone metabolism (2,50,63).…”

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confidence: 99%

“…Two groups of data with normal distribution were compared by unpaired Figs. 3,7,and 8), whereas data with nonnormal distribution were compared by nonparametric Mann-Whitney test (i.e., Figs. 1,2,4,5,6,and 9).…”

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confidence: 99%

Running exercise alleviates trabecular bone loss and osteopenia in hemizygous β-globin knockout thalassemic mice

Thongchote

American Journal of Physiology-Endocrinology and Metabolism

et al. 2014

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Thongchote K, Svasti S, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N. Running exercise alleviates trabecular bone loss and osteopenia in hemizygous ␤-globin knockout thalassemic mice. Am J Physiol Endocrinol Metab 306: E1406 -E1417, 2014. First published April 29, 2014; doi:10.1152/ajpendo.00111.2014.-A marked decrease in ␤-globin production led to ␤-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous ␤-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1-2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast-mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1␣ and -1␤. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in ␤-thalassemia. bone histomorphometry; bone mineral density; endurance exercise; running wheel; osteoporosis HEMOGLOBIN-OXYGEN-CARRYING METALLOPROTEIN in the erythrocytes-is composed of two ␣-globin chains and two ␤-globin chains. Inadequate production or absence of ␤-globin is found in a hereditary disease known as ␤-thalassemia, which is a common autosomal recessive anemic disorder in several populations, such as Chinese, Southeast Asian, and Mediterranean populations (6,15,34,59). Thalassemic patients and rodents both manifest ineffective erythropoiesis, extramedullary erythropoiesis, splenomegaly, iron overload, growth retardation, short stature, and skeletal deformity (16,28,31,38,43,56,62). However, little is known regarding the detailed changes in bone mineral density (BMD) and microstructural defect as well as the cellular mechanism of bone loss, especially at the early stages of the disease in young growing and adolescent mice.Our recent study has provided evidence that defective bone matrix ...