MacIntyre I, Zaidi M, Alam A S, Datta H K, Moonga B S, Lidbury P S, Hecker M, Vane J R
Department of Medicine and Chemical Pathology, Royal Postgraduate Medical School, London, United Kingdom.
Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2936-40. doi: 10.1073/pnas.88.7.2936.
The osteoclast is unique in its ability to resorb bone, and excessive osteoclastic activity has been implicated in osteoporosis, Paget disease of bone, rheumatoid arthritis, and the growth of metastases in bone. The activity of this cell is controlled by the main circulating inhibitor, calcitonin, in association with locally produced modulators. We show that nitric oxide (NO) may be an important member of the latter group. NO is produced by the vascular endothelium and nervous system and is involved in both neurotransmission and the regulation of blood pressure. However, our results show that the autocoid is also a potent inhibitor of osteoclast function. NO (30 microM) produced a decrease to approximately 50% of the original osteoclast spread area. Similar effects were also produced by 3-morpholinosydnonimine or sodium nitroprusside, reagents that spontaneously release NO. These shape changes were associated with a reduction of bone resorption after a 24-hr incubation of isolated osteoclasts on devitalized bone slices. NO is thought to act by stimulating guanylate cyclase, with a consequent increase in cyclic GMP, but a different mode of action is likely in the osteoclast since dibutyryl or 8-bromo cyclic GMP have no effect. It should be noted that calcitonin can produce similar changes in shape and activity but is associated with an increase in osteoclast intracellular calcium and cessation of membrane movement; neither of these is produced by NO, suggesting that its mode of action is different. The abundance of NO-producing endothelial cells in bone marrow and their proximity to osteoclasts suggests that marrow endothelial cells may play a physiological role in the regulation of osteoclastic activity.
破骨细胞在骨吸收能力方面独具特色，破骨细胞活性过度与骨质疏松症、骨Paget病、类风湿性关节炎以及骨转移瘤的生长有关。该细胞的活性由主要的循环抑制剂降钙素以及局部产生的调节剂共同控制。我们发现一氧化氮（NO）可能是后者中的重要一员。NO由血管内皮和神经系统产生，参与神经传递和血压调节。然而，我们的结果表明，这种自体活性物质也是破骨细胞功能的有效抑制剂。NO（30 microM）可使破骨细胞的铺展面积减少至原来的约50%。3 - 吗啉代辛二亚胺或硝普钠等可自发释放NO的试剂也产生了类似效果。这些形态变化与在失活骨切片上分离的破骨细胞孵育24小时后骨吸收的减少有关。NO被认为是通过刺激鸟苷酸环化酶起作用，从而导致环磷酸鸟苷（cGMP）增加，但在破骨细胞中可能存在不同的作用模式，因为二丁酰或8 - 溴环磷酸鸟苷没有效果。应当注意的是，降钙素可产生类似的形态和活性变化，但与破骨细胞内钙增加和膜运动停止有关；而这些都不是由NO产生的，这表明其作用模式不同。骨髓中产生NO的内皮细胞丰富且与破骨细胞相邻，提示骨髓内皮细胞可能在破骨细胞活性调节中发挥生理作用。
