Abstract
β-thalassemia is often associated with hyperglycemia, osteoporosis and increased fracture risk. However, the underlying mechanisms of the thalassemia-associated bone loss remain unclear. It might result from abnormal activities of osteoblasts and osteoclasts, and perhaps prolonged exposure to high extracellular glucose. Herein, we determined the rate of duodenal calcium transport in hemizygous β-globin knockout thalassemic (BKO) mice. Their bones were collected for primary osteoblast and osteoclast culture. We found that BKO mice had lower calcium absorption than their wild-type (WT) littermates. Osteoblasts from BKO mice showed aberrant expression of osteoblast-specific genes, e.g., Runx2, alkaline phosphatase and osteocalcin, which could be partially restored by 1,25(OH)2D3 treatment. However, the mRNA expression levels of RANK, calcitonin receptor (Calcr), c-Fos, NFATc1, cathepsin K and DMT1 were similar in both BKO and WT groups. Exposure to high extracellular glucose modestly but significantly affected the expression of osteoclast-specific markers in WT osteoclasts with no significant effect on osteoblast-specific genes in WT osteoblasts. Thus, high glucose alone was unable to convert WT bone cells to BKO-like bone cells. In conclusion, the impaired calcium absorption and mutation-related aberrant bone cell function rather than exposure to high blood glucose were likely to be the principal causes of thalassemic bone loss.
Highlights
Β-thalassemia—a hereditary anemic disease caused by loss-of-function mutation of β-globin gene1—has been reported to cause a number of complications, including ineffective erythropoiesis, growth retardation, osteoporosis, hyperglycemia and diabetes mellitus (DM)[2]
The objectives of the present study were (i) to confirm the presence of aberrant calcium metabolism in BKO versus wild-type (WT) mice; (ii) to determine the mRNA expression of osteoblast- and osteoclast-related markers in primary osteoblasts and osteoclasts derived from BKO mice; (iii) to find out whether 1,25(OH)2D3 was able to rescue the expression of bone markers; and (iv) to investigate the responses of primary osteoblasts and osteoclasts from WT mice to high extracellular glucose and observe whether they exhibited similar abnormalities as BKO bone cells or were converted to BKO-like cells
We found that 1,25(OH)2D3 pretreatment reduced the expression of insulin receptor (INSR) in primary osteoblasts from WT, but increased INSR expression in cells from BKO mice when compared with 1,25(OH)2D3-treated WT group (Fig. 3B)
Summary
Β-thalassemia—a hereditary anemic disease caused by loss-of-function mutation of β-globin gene1—has been reported to cause a number of complications, including ineffective erythropoiesis, growth retardation, osteoporosis, hyperglycemia and diabetes mellitus (DM)[2]. Our previous investigations in hemizygous β-globin knockout thalassemic (BKO) mice indicated that the thalassemia-associated bone loss was partially caused by chronic exposure to inflammatory cytokines [e.g., interleukin (IL)−1α and −1β)], which tremendously enhanced osteoclastogenesis and osteoclast-mediated bone resorption and decreased bone formation[3]. The objectives of the present study were (i) to confirm the presence of aberrant calcium metabolism in BKO versus wild-type (WT) mice; (ii) to determine the mRNA expression of osteoblast- and osteoclast-related markers in primary osteoblasts and osteoclasts derived from BKO mice; (iii) to find out whether 1,25(OH)2D3 was able to rescue the expression of bone markers; and (iv) to investigate the responses of primary osteoblasts and osteoclasts from WT mice to high extracellular glucose and observe whether they exhibited similar abnormalities as BKO bone cells or were converted to BKO-like cells. We used 9-week-old female mice for isolating primary bone cells because our previous in vivo study has demonstrated that they clearly manifested osteopenia after 8 weeks of age as assessed by dual-energy x-ray absorptiometry and bone histomorphometry[3]
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