A distinct pattern of cytokine production from blood mononuclear cells in multitransfused patients with β-thalassaemia

Salsaa, B.; Zoumbos, Nicholas

doi:10.1046/j.1365-2249.1997.d01-962.x

Cited by 21 publications

(13 citation statements)

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“…Reactive oxygen species also stimulated osteoclast differentiation and bone resorption (3). Meanwhile, the ␤-thalassemia-induced ineffective erythropoiesis promoted a tremendous production of proinflammatory cytokines, e.g., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)␣, all of which were reported to suppress osteoblast differentiation and augment osteoclastogenesis (23,31,36). The lack of osteogenic stimulation by certain endocrine factors, especially IGF-I, which was reported to be ϳ65% lower in ␤-thalassemia patients than in healthy individuals (10), could further deteriorate osteoblast activity, as indicated by low serum osteocalcin levels in ␤-thalassemia patients (10).…”

Section: Discussionmentioning

confidence: 99%

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

Thongchote

Svasti

Teerapornpuntakit

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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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...

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Section: Discussionmentioning

confidence: 99%

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

Thongchote

Svasti

Teerapornpuntakit

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Since oxidative stress-related chronic inflammation and compensatory increase in erythropoiesis were accompanied by intramedullary hematopoietic cytokine release (26,41), osteoclast precursor cells that were also derived from hematopoietic stem cells could proliferate concurrently (18), thus leading to an exaggerated number of active osteoclasts. IL-1 was capable of activating the transcription of osteoclast-specific genes, such as tartrateresistant acid phosphatase (TRAP) and osteoclast maturation (32).…”

Section: Discussionmentioning

confidence: 99%

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

Thongchote

Svasti

Teerapornpuntakit

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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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 ...

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“…Indirect evidence of increased and prolonged tissue injury in thalassemic and sickle patients includes activation of polymorphonuclear neutrophils and monocytes and the increased levels of neutrophil elastase and circulating cytokines. 49,64,[69][70][71][72] It should be stated that of all hemoglobinopathies, ␤ thalassemia is the most informative in terms of elastic tissue abnormalities. Extensive clinical and histologic findings have been presented in the literature.…”

Section: Pathogenesis and Geneticsmentioning

confidence: 99%

Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes

Aessopos

Farmakis

Loukopoulos

2002

Blood

139

124

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The development of clinical and histopathologic manifestations of a diffuse elastic tissue defect, resembling inherited pseudoxanthoma elasticum (PXE), has been encountered with a notable frequency in patients with ␤ thalassemia, sickle cell disease, and sickle thalassemia. The PXE-like clinical syndrome, consisting of skin, ocular, and vascular manifestations, has a variable severity in these hemoglobinopathies and it is age-dependent, with a generally late onset, after the second decade of life. The defect is believed to be acquired rather than inherited and related to the consequences of the primary disease. The high prevalence of the findings implicates the elastic tissue injury as one of the main comorbid abnormalities encountered in ␤ thalassemia and the sickling syndromes. In these patients a number of complications, sometimes serious, has been recognized to be related to ocular and vascular elastic tissue defects. Because several organ systems are involved, each medical specialty should be aware of the phenomenon. This coexistence, on the other hand, introduces a novel pathogenetic aspect of PXE and an important research challenge. (Blood. 2002;99:30-35)

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A distinct pattern of cytokine production from blood mononuclear cells in multitransfused patients with β-thalassaemia

Cited by 21 publications

References 5 publications

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

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

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

Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes

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A distinct pattern of cytokine production from blood mononuclear cells in multitransfused patients with β-thalassaemia

Cited by 21 publications

References 5 publications

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

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

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

Elastic tissue abnormalities resembling pseudoxanthoma elasticum in β thalassemia and the sickling syndromes

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

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