CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption
CCAAT/enhancer binding protein β-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption
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DOI：
10.1152/ajpregu.00764.2010
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发表时间：
2011-05-01
影响因子：
2.8
通讯作者：
McCabe, Laura R.
中科院分区：
文献类型：
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作者：
Motyl, Katherine J.;Raetz, Michelle;McCabe, Laura R.
Motyl KJ、Raetz M、Tekalur SA、Schwartz RC、McCabe LR。 CCAAT/增强子结合蛋白β缺陷通过增加骨髓脂肪和骨吸收来增强1型糖尿病骨表型。 Am J Physiol Regul Integr Comp Physiol 300：R1250-R1260，2011。首次发表于 2011 年 2 月 23 日； doi:10.1152/ajpregu.00764.2010.-1 型糖尿病的骨质流失伴随着骨髓脂肪的增加，这可能直接降低成骨细胞活性或由改变的骨髓间充质细胞谱系选择（脂肪细胞与成骨细胞）引起。 CCAAT/增强子结合蛋白β（C/EBPβ）是脂肪细胞和成骨细胞分化的重要调节因子。 C/EBP β 缺失小鼠的骨形成延迟，棕色脂肪组织中的脂质积累有缺陷。为了检查糖尿病背景下 C/EBP β 功能的平衡，我们在 C/EBP β 缺失（敲除，KO）小鼠中诱导 1 型糖尿病。我们发现 C/EBP β 缺乏实际上增强了糖尿病骨表型。虽然与野生型小鼠相比，KO 小鼠的外周脂肪量有所减少，但它们的骨髓脂肪细胞比糖尿病野生型小鼠多 5 倍。骨髓肥胖的增加可能归因于 C/EBP β、过氧化物酶体增殖物激活受体 γ 2 和 C/EBP α 的补偿。同时，我们观察到骨密度降低。相对于基因型对照，糖尿病 KO 小鼠的骨小梁体积分数损失 (-48%) 与糖尿病野生型小鼠 (-22%) 的变化相比有所增加。尽管骨质流失较多，但糖尿病 KO 小鼠中的成骨细胞标记物并未进一步受到抑制。相反，KO 糖尿病小鼠的破骨细胞标记物有所增加。因此，C/EBPβ缺乏会增加糖尿病引起的骨髓（而非外周）脂肪库质量，并通过刺激骨吸收促进额外的骨质流失。 C/EBP β 缺乏也会降低骨硬度，而糖尿病则加剧了这种情况（双向方差分析 P < 0.02）。我们的结论是，单独的 C/EBP β 并不导致 T1 型糖尿病中观察到的骨与脂肪表型转换，并且抑制 CEBP β 水平可能会通过增加骨吸收来进一步骨质流失并降低骨硬度。
Motyl KJ, Raetz M, Tekalur SA, Schwartz RC, McCabe LR. CCAAT/enhancer binding protein beta-deficiency enhances type 1 diabetic bone phenotype by increasing marrow adiposity and bone resorption. Am J Physiol Regul Integr Comp Physiol 300: R1250-R1260, 2011. First published February 23, 2011; doi:10.1152/ajpregu.00764.2010.-Bone loss in type 1 diabetes is accompanied by increased marrow fat, which could directly reduce osteoblast activity or result from altered bone marrow mesenchymal cell lineage selection (adipocyte vs. osteoblast). CCAAT/enhancer binding protein beta (C/EBP beta) is an important regulator of both adipocyte and osteoblast differentiation. C/EBP beta-null mice have delayed bone formation and defective lipid accumulation in brown adipose tissue. To examine the balance of C/EBP beta functions in the diabetic context, we induced type 1 diabetes in C/EBP beta-null (knockout, KO) mice. We found that C/EBP beta deficiency actually enhanced the diabetic bone phenotype. While KO mice had reduced peripheral fat mass compared with wild-type mice, they had 5-fold more marrow adipocytes than diabetic wild-type mice. The enhanced marrow adiposity may be attributed to compensation by C/EBP beta, peroxisome proliferator-activated receptor-gamma 2, and C/EBP alpha. Concurrently, we observed reduced bone density. Relative to genotype controls, trabecular bone volume fraction loss was escalated in diabetic KO mice (-48%) compared with changes in diabetic wild-type mice (-22%). Despite greater bone loss, osteoblast markers were not further suppressed in diabetic KO mice. Instead, osteoclast markers were increased in the KO diabetic mice. Thus, C/EBP beta deficiency increases diabetes-induced bone marrow (not peripheral) adipose depot mass, and promotes additional bone loss through stimulating bone resorption. C/EBP beta-deficiency also reduced bone stiffness and diabetes exacerbated this (two-way ANOVA P < 0.02). We conclude that C/EBP beta alone is not responsible for the bone vs. fat phenotype switch observed in T1 diabetes and that suppression of CEBP beta levels may further bone loss and decrease bone stiffness by increasing bone resorption.