Widespread Increase in Myeloid Calcifying Cells Contributes to Ectopic Vascular Calcification in Type 2 Diabetes
Widespread Increase in Myeloid Calcifying Cells Contributes to Ectopic Vascular Calcification in Type 2 Diabetes
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DOI：
10.1161/circresaha.110.234088
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发表时间：
2011-04-29
影响因子：
20.1
通讯作者：
Avogaro, Angelo
中科院分区：
文献类型：
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作者：
Fadini, Gian Paolo;Albiero, Mattia;Avogaro, Angelo
目的：我们的目标是鉴定和表征循环中的钙化细胞，并描述这些细胞在2型糖尿病中的病理生理作用。方法和结果：我们首次证明了在体外和体内，表达骨钙素和骨碱性磷酸酶(OC(+)BAP(+))的循环细胞亚群具有促钙化活性。对初治的慢性髓系白血病患者的研究表明，OC(+)BAP(+)细胞起源于髓系。骨髓样钙化OC(+)BAP(+)细胞(MCC)可从外周血单核细胞分化而来，MCC的产生与成骨转录因子Runx2的表达密切相关。在性别不匹配的骨髓移植患者中，与OC(-)BAP(-)细胞相比，循环中的MCC具有更长的半衰期，表明它们属于稳定的细胞库。与对照组相比，2型糖尿病患者外周血和骨髓中MCC的比例较高，但通过优化血糖控制，MCC的比例降至正常水平。此外，糖尿病颈动脉内膜切除术标本显示钙化程度更高，钙化结节周围的α-平滑肌肌动蛋白阴性区有大量OC和BAP表达的细胞，CD68(+)巨噬细胞在那里共存。高糖在体外可促进MCC的钙化，低氧在体外和体内可能调节MCC的生成。结论：这些数据证实了一种新型的血源性前钙细胞，可能参与糖尿病患者的动脉粥样硬化性钙化。(中国保监会决议，2011；108：1112-1121。)
Rationale: Acquisition of a procalcific phenotype by resident or circulating cells is important for calcification of atherosclerotic plaques, which is common in diabetes.Objective: We aim to identify and characterize circulating calcifying cells, and to delineate a pathophysiological role for these cells in type 2 diabetes.Methods and Results: We demonstrate for the first time that a distinct subpopulation of circulating cells expressing osteocalcin and bone alkaline phosphatase (OC(+)BAP(+)) has procalcific activity in vitro and in vivo. The study of naive patients with chronic myeloid leukemia indicated that OC(+)BAP(+) cells have a myeloid origin. Myeloid calcifying OC(+)BAP(+) cells (MCCs) could be differentiated from peripheral blood mononuclear cells, and generation of MCCs was closely associated with expression of the osteogenic transcription factor Runx2. In gender-mismatched bone marrow-transplanted humans, circulating MCCs had a much longer half-life compared with OC(-)BAP(-) cells, suggesting they belong to a stable cell repertoire.The percentage of MCCs was higher in peripheral blood and bone marrow of type 2 diabetic patients compared with controls but was lowered toward normal levels by optimization of glycemic control. Furthermore, diabetic carotid endoarterectomy specimens showed higher degree of calcification and amounts of cells expressing OC and BAP in the alpha-smooth muscle actin-negative areas surrounding calcified nodules, where CD68(+) macrophages colocalize. High glucose increased calcification by MCCs in vitro, and hypoxia may regulate MCC generation in vitro and in vivo.Conclusions: These data identify a novel type of blood-derived procalcific cells potentially involved in atherosclerotic calcification of diabetic patients. (Circ Res. 2011;108:1112-1121.)