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

Abstract

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 ...

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

“…The present results, however, suggest that ␤-thalassemia might interfere with osteoblast and osteoclast functions. Specifically, osteoblast surface was significantly reduced in ␤ IVSII-654 thalassemic mice, similarly to that observed previously in BKO mice (31), indicating that there were fewer numbers of active osteogenic cells. Since iron could induce oxidative stress and apoptosis of osteoblasts as a result of Fenton and Haber-Weiss reactions (29), iron accumulation in bone tissue might contribute to this reduction in osteoblast surface.…”

“…Without estradiol levels, we cannot be certain that low estradiol played a role in these mice. At the microstructural level, decreases in trabecular bone volume fraction and trabecular number were conspicuously observed in both male and female ␤ IVSII-654 mice, similar to those observed in hemizygous BKO mice (31). However, trabecular defects appeared to be more severe in female ␤ mice, as they manifested a marked decrease in trabecular thickness at 1-4 mo old, whereas the male ␤ IVSII-654 littermates showed no change in trabecular thickness at 2 and 4 mo of age compared with the male wild-type mice.…”

“…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).…”

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

“…Dysregulation of calcium metabolism was one of the most important metabolic disturbances in ␤-thalassemia, leading to osteopenia, osteoporosis, and fracture in humans and rodents (41,43). In an attempt to explore the cause of osteopenia in thalassemia, we demonstrated herein that both transcellular and paracellular calcium fluxes in the duodenum of BKO mice were much reduced compared with those in the WT littermate.…”

Engraftment and bone mass are enhanced by PTHrP 1–34 in ectopically transplanted vertebrae (vossicle model) and can be non-invasively monitored with bioluminescence and fluorescence imaging

“…Since we implanted vertebrae from 5-day-old mice, the implants are ~3 to 5 weeks of age after 2 and 4 weeks. There is a normal decrease in the trabecular bone percentage in mice from ~1 to 2 months of age (Moverare-Skrtic et al 2014; Thongchote et al 2014). Therefore, the decrease in the percentage of total and trabecular bone between 2 and 4 weeks partially results from normal age-related changes.…”