Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption
Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption
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DOI：
10.1096/fj.02-0205com
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发表时间：
2003-03-01
期刊：
影响因子：
4.8
通讯作者：
Zaidi, M
中科院分区：
文献类型：
--
作者：
Sun, L;Iqbal, J;Zaidi, M
我们已经评估了ADP-核糖基环化酶，CD 38，在骨重建，骨骼不断更新的过程中，通过破骨细胞和成骨细胞的协调活动的作用。CD 38催化其底物NAD（+）环化为释放Ca 2+的第二信使环ADP核糖（cADPr）。我们以前已经表明，CD 38在成骨细胞和破骨细胞中表达。其在破骨细胞中的活化通过兰尼碱受体（RyRs）触发Ca 2+释放，刺激白细胞介素-6（IL-6），并抑制骨吸收。在这里，我们研究了删除小鼠CD 38基因对骨骼重塑的影响。我们报告称，CD 38（-/-）小鼠在3个月时股骨、胫骨和腰椎骨密度（BMD）显著降低，4个月时腰椎骨密度显著降低，5个月时所有部位BMD完全正常化。3个月时的骨质疏松症伴随着组织形态学分析中原发性松质骨减少和破骨细胞表面增加。从CD 38（-/-）小鼠离体分离的造血干细胞显示，与RANK-L和M-CSF孵育6天后，破骨细胞形成显著增加至4倍。与野生型细胞相比，在这些培养物中形成的破骨细胞显示出类似于2.5倍的吸收活性增加。然而，当贴壁骨髓基质细胞被允许成熟为碱性磷酸酶阳性集落形成单位（CFU-Fs），那些来自CD 38（-/-）小鼠显示出显着减少的分化与野生型细胞相比。对第6天从破骨细胞中分离的mRNA进行实时RTPCR，结果显示IL-6和IL-6受体mRNA显著降低，同时所有钙调磷酸酶A亚型α、β和γ的表达显著降低。这些发现确立了CD 38在破骨细胞形成和骨吸收中的关键作用。我们推测，CD 38作为细胞NAD（+）的“传感器”，特别是在活跃的运动和分泌期间。
We have evaluated the role of the ADP-ribosyl cyclase, CD38, in bone remodeling, a process by which the skeleton is being renewed constantly through the coordinated activity of osteoclasts and osteoblasts. CD38 catalyzes the cyclization of its substrate, NAD(+),to the Ca2+-releasing second messenger, cyclic ADP-ribose (cADPr). We have shown previously that CD38 is expressed both in osteoblasts and osteoclasts. Its activation in the osteoclast triggers Ca2+ release through ryanodine receptors (RyRs), stimulation of interleukin-6 (IL-6), and an inhibition of bone resorption. Here, we have examined the consequences of deleting the CD38 gene in mice on skeletal remodeling. We report that CD38(-/-) mice displayed a markedly reduced bone mineral density (BMD) at the femur, tibia, and lumbar spine at 3 months and at the lumbar spine at 4 months, with full normalization of the BMD at all sites at 5 months. The osteoporosis at 3 months was accompanied by a reduction in primary spongiosa and increased osteoclast surfaces on histomorphometric analysis. Hematopoetic stem cells isolated ex vivo from CD38(-/-) mice showed a dramatic similar tofourfold increase in osteoclast formation in response to incubation for 6 days with RANK-L and M-CSF. The osteoclasts so formed in these cultures showed a similar to2.5-fold increase in resorptive activity compared with wild-type cells. However, when adherent bone marrow stromal cells were allowed to mature into alkaline phosphatase-positive colony-forming units (CFU-Fs), those derived from CD38(-/-) mice showed a significant reduction in differentiation compared with wild-type cells. Real-time RTPCR on mRNA isolated from osteoclasts at day 6 showed a significant reduction in IL-6 and IL-6 receptor mRNA, together with significant decreases in the expression of all calcineurin A isoforms, alpha, beta, and gamma. These findings establish a critical role for CD38 in osteoclast formation and bone resorption. We speculate that CD38 functions as a cellular NAD(+) "sensor," particularly during periods of active motility and secretion.