Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation
Nitric oxide modulates bone anabolism through regulation of osteoblast glycolysis and differentiation
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DOI：
10.1172/jci138935
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发表时间：
2021-03-01
影响因子：
15.9
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
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作者：
Jin, Zixue;Kho, Jordan;Lee, Brendan
以前的研究表明，一氧化氮（NO）补充剂可以预防雌激素缺乏的临床前模型中的骨丢失和骨折。然而，NO调节骨愈合的机制仍不清楚。精氨酸琥珀酸裂解酶（ASL）是唯一能够合成精氨酸的哺乳动物酶，精氨酸是一氧化氮合酶依赖性（NOS依赖性）NO合成的唯一前体。此外，ASL还需要将细胞外精氨酸引导至NOS以产生NO。ASL缺乏症（ASLD）是研究细胞自主性、NOS依赖性NO缺乏症的模型。在这里，我们报告说，ASL的损失导致减少NO的生产和损伤的成骨细胞分化。从机制上讲，骨表型至少部分是由成骨细胞中NO介导的糖酵解途径活化的丧失驱动的，这导致成骨细胞分化和功能降低。小窝蛋白1的杂合性缺失，一种NO合成的负调节因子，恢复了ASLD的低形态小鼠模型中的NO产生、成骨细胞分化、糖酵解和骨量。这些临床前研究的转化意义通过在来自ASLD个体的诱导多能干细胞中进行的研究进一步重申。总之，我们的研究结果表明，ASLD是一个独特的遗传模型，研究NO依赖性成骨细胞的功能和NO/糖酵解途径可能是一个新的目标，以调节骨愈合。
Previous studies have shown that nitric oxide (NO) supplements may prevent bone loss and fractures in preclinical models of estrogen deficiency. However, the mechanisms by which NO modulates bone anabolism remain largely unclear. Argininosuccinate lyase (ASL) is the only mammalian enzyme capable of synthesizing arginine, the sole precursor for nitric oxide synthase-dependent (NOS-dependent) NO synthesis. Moreover, ASL is also required for channeling extracellular arginine to NOS for NO production. ASL deficiency (ASLD) is thus a model to study cell-autonomous, NOS-dependent NO deficiency. Here, we report that loss of ASL led to decreased NO production and impairment of osteoblast differentiation. Mechanistically, the bone phenotype was at least in part driven by the loss of NO-mediated activation of the glycolysis pathway in osteoblasts that led to decreased osteoblast differentiation and function. Heterozygous deletion of caveolin 1, a negative regulator of NO synthesis, restored NO production, osteoblast differentiation, glycolysis, and bone mass in a hypomorphic mouse model of ASLD. The translational significance of these preclinical studies was further reiterated by studies conducted in induced pluripotent stem cells from an individual with ASLD. Taken together, our findings suggest that ASLD is a unique genetic model for studying NO-dependent osteoblast function and that the NO/glycolysis pathway may be a new target to modulate bone anabolism.