Krieger Nancy S, Frick Kevin K, Bushinsky David A
Department of Medicine, Nephrology Unit, University of Rochester School of Medicine, Rochester, New York 14642, USA.
J Am Soc Nephrol. 2002 Oct;13(10):2534-9. doi: 10.1097/01.asn.0000031721.19801.7c.
Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro, metabolic acidosis has been shown to initially induce physicochemical mineral dissolution and then enhance cell-mediated bone resorption. Acidic medium stimulates osteoblastic prostaglandin E(2) production, which mediates the subsequent stimulation of osteoclastic bone resorption. Glucocorticoids are also known to decrease bone mineral density, and metabolic acidosis has been shown to increase glucocorticoid production. This study tested the hypothesis that glucocorticoids would exacerbate acid-induced net calcium efflux from bone. Neonatal mouse calvariae were cultured in acid (Acid; pH = 7.06 +/- 0.01; [HCO(3)(-)] = 10.6 +/- 0.3 mM) or neutral (Ntl; pH = 7.43 +/- 0.01; [HCO(3)(-)] = 26.2 +/- 0.5 mM) medium, with or without 1 microM cortisol (Cort), and net calcium efflux and medium prostaglandin E(2) (PGE(2)) levels and osteoclastic beta-glucuronidase activity were determined. Compared with Ntl, Cort alone decreased calcium efflux, medium PGE(2), and osteoclast activity; Acid led to an increase in all three parameters. The addition of Cort to Acid led to a reduction of calcium efflux, medium PGE(2) levels and beta-glucuronidase activity compared with Acid alone. There was a significant direct correlation between medium PGE(2) concentration and net calcium efflux (r = 0.944; n = 23; P < 0.0001), between osteoclastic beta-glucuronidase activity and net calcium efflux (r = 0.663; n = 40; P < 0.001), and between medium PGE(2) concentration and beta-glucuronidase activity (r = 0.976; n = 4; P < 0.01). Thus, in vitro cortisol inhibits acid-induced, cell-mediated osteoclastic bone resorption through a decrease in osteoblastic PGE(2) production. These results suggest that the osteopenia observed in response to metabolic acidosis in vivo is not due to an increase in endogenous cortisol production.
代谢性酸中毒会增加尿钙排泄，而不会增加肠道钙吸收，从而导致骨矿物质净流失。在体外实验中，已表明代谢性酸中毒最初会诱导物理化学性矿物质溶解，然后增强细胞介导的骨吸收。酸性培养基会刺激成骨细胞产生前列腺素E(2)，后者介导随后对破骨细胞骨吸收的刺激作用。已知糖皮质激素也会降低骨矿物质密度，并且已表明代谢性酸中毒会增加糖皮质激素的产生。本研究检验了以下假设：糖皮质激素会加剧酸诱导的骨钙净流出。将新生小鼠颅骨在酸性（酸组；pH = 7.06 ± 0.01；[HCO₃⁻] = 10.6 ± 0.3 mM）或中性（对照组；pH = 7.43 ± 0.01；[HCO₃⁻] = 26.2 ± 0.5 mM）培养基中培养，添加或不添加1 μM皮质醇（Cort），并测定钙净流出、培养基中前列腺素E(2)（PGE₂）水平和破骨细胞β-葡萄糖醛酸酶活性。与对照组相比，单独使用皮质醇会降低钙流出、培养基中PGE₂和破骨细胞活性；酸组导致这三个参数均增加。与单独使用酸组相比，在酸组中添加皮质醇会导致钙流出、培养基中PGE₂水平和β-葡萄糖醛酸酶活性降低。培养基中PGE₂浓度与钙净流出之间存在显著的直接相关性（r = 0.944；n = 23；P < 0.0001），破骨细胞β-葡萄糖醛酸酶活性与钙净流出之间存在显著的直接相关性（r = 0.663；n = 40；P < 0.001），培养基中PGE₂浓度与β-葡萄糖醛酸酶活性之间存在显著的直接相关性（r = 0.976；n = 4；P < 0.01）。因此，在体外，皮质醇通过减少成骨细胞PGE₂的产生来抑制酸诱导的、细胞介导的破骨细胞骨吸收。这些结果表明，体内因代谢性酸中毒而观察到的骨质减少并非由于内源性皮质醇产生增加所致。
