Turner C H, Owan I, Jacob D S, McClintock R, Peacock M
Department of Orthopaedic Surgery, Indiana University Medical Center, Indianapolis 46202, USA.
Bone. 1997 Dec;21(6):487-90. doi: 10.1016/s8756-3282(97)00202-0.
NO is synthesized from L-arginine by at least three isoforms of nitric oxide synthase (NOS) and is known to function as a vasodilator and neurotransmitter. NO is produced by bone cells but its function in bone biology is, as yet, unclear. We hypothesized that NOS mediates bone formation in remodeling regions of the skeleton. We studied the effects of two NOS inhibitors: N(G)-nitro-L-arginine methyl ester (L-NAME), which is a general inhibitor of NOS activity and is known to inhibit the vasodilatory effects of the endothelial NOS (eNOS) isoform; and aminoguanidine, which is a selective inhibitor of the inducible NOS (iNOS) isoform. Our hypothesis was tested by treating rats with NOS inhibitors and measuring bone formation rates in the tibial epiphysis and diaphysis. Bone formation indices were measured using standard bone histomorphometry. L-NAME treatment significantly raised mean arterial blood pressure (MAP). This effect was partially reversed by addition of L-arginine. Aminoguanidine had no significant effect on MAP, indicating that it did not block eNOS. The treatments also had substantial effects on bone formation in remodeling trabecular bone. L-NAME did not significantly change trabecular bone formation rate, whereas aminoguanidine reduced bone formation rate in the tibial epiphysis by 79% compared with control. This reduction was completely reversed by L-arginine, suggesting that bone formation during remodeling is, in part, mediated through L-arginine metabolism. No effect of aminoguanidine on bone formation was seen in the tibial diaphysis, a site that undergoes minimal bone remodeling. This finding suggests that the L-arginine-NO pathway is important in bone remodeling.
一氧化氮（NO）由一氧化氮合酶（NOS）的至少三种同工型从L-精氨酸合成，已知其具有血管舒张剂和神经递质的功能。骨细胞可产生NO，但其在骨生物学中的功能尚不清楚。我们推测NOS介导骨骼重塑区域的骨形成。我们研究了两种NOS抑制剂的作用：N（G）-硝基-L-精氨酸甲酯（L-NAME），它是NOS活性的通用抑制剂，已知可抑制内皮型NOS（eNOS）同工型的血管舒张作用；以及氨基胍，它是诱导型NOS（iNOS）同工型的选择性抑制剂。通过用NOS抑制剂处理大鼠并测量胫骨骨骺和骨干的骨形成率来检验我们的假设。使用标准骨组织形态计量学测量骨形成指标。L-NAME处理显著提高了平均动脉血压（MAP）。添加L-精氨酸可部分逆转这种作用。氨基胍对MAP没有显著影响，表明它没有阻断eNOS。这些处理对重塑的小梁骨中的骨形成也有显著影响。L-NAME没有显著改变小梁骨形成率，而氨基胍使胫骨骨骺的骨形成率与对照组相比降低了79%。这种降低被L-精氨酸完全逆转，表明重塑过程中的骨形成部分是通过L-精氨酸代谢介导的。在胫骨骨干（一个骨重塑极少的部位）未观察到氨基胍对骨形成有影响。这一发现表明L-精氨酸-NO途径在骨重塑中很重要。
