Changes in Bone Microarchitecture and Biomechanical Properties in the th3 Thalassemia Mouse are Associated with Decreased Bone Turnover and Occur During the Period of Bone Accrual

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Abstract
Osteoporosis and fractures occur frequently in patients with β-thalassemias, a group of congenital hemolytic anemias characterized by decreased synthesis of the β chain of hemoglobin. In this study, we determined the bone abnormalities of the th3 thalassemia mouse, generated by deletion of the mouse β-chain genes. The heterozygous th3/+ mouse has moderate anemia and serves as a model of β-thalassemia intermedia, which represents the mild thalassemia phenotype. The th3/th3 mouse has lethal anemia and is a model of β-thalassemia major, which is characterized by life-threatening anemia requiring regular transfusions to sustain life. Compared to controls, (1) μCT of trabecular bone showed decreased bone volume fraction, number of trabeculae, and trabecular thickness in both th3/+ and th3/th3 (P < 0.05); (2) cortical bone analysis showed thinner cortices and increased marrow area in th3/+ (P < 0.05); (3) μCT abnormalities in th3/+ mice were present by 2 months and did not worsen with age; (4) histomorphometry was significant for decreased bone formation and resorption in both th3/+ and th3/th3, and expression of cathepsin K and osteocalcin from bone of both th3/+ and th3/th3 animals was reduced (P < 0.05); (5) biomechanics showed reduced maximum load, maximum moment, and structural stiffness in both th3/+ and th3/th3 (P < 0.01). In conclusion, the th3 mouse model of thalassemia manifests bone changes reminiscent of those in humans and can be used for further bone studies in thalassemia. Bone changes are associated with decreased bone turnover and develop early during the period of bone accrual.

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