Cortisol Inhibits Acid-Induced Bone Resorption In Vitro

Abstract

Abstract. 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 ϭ 7.06 Ϯ 0.01; [HCO 3 Ϫ ] ϭ 10.6 Ϯ 0.3 mM) or neutral (Ntl; pH ϭ 7.43 Ϯ 0.01; [HCO 3 Ϫ ] ϭ 26.2 Ϯ 0.5 mM) medium, with or without 1 M cortisol (Cort), and net calcium efflux and medium prostaglandin E 2 (PGE 2 ) levels and osteoclastic ␤-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 ␤-glucuronidase activity compared with Acid alone. There was a significant direct correlation between medium PGE 2 concentration and net calcium efflux (r ϭ 0.944; n ϭ 23; P Ͻ 0.0001), between osteoclastic ␤-glucuronidase activity and net calcium efflux (r ϭ 0.663; n ϭ 40; P Ͻ 0.001), and between medium PGE 2 concentration and ␤Ϫglucuronidase activity (r ϭ 0.976; n ϭ 4; P Ͻ 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.

Mechanism of acid-induced bone resorption

“…The magnitude of this acid-induced increase in medium prostaglandin E 2 levels of primary bone cells was comparable to that observed in cultured calvariae incubated in acid medium. We also found that cortisol inhibits acid-induced bone resorption through a decrease in osteoblastic prostaglandin E 2 production [113]. These results suggest that acid-induced, cell-mediated calcium efflux from bone is regulated, at least partly, by an increase in endogenous prostaglandin E 2 production.…”

Metabolic acidosis in maintenance dialysis patients: Clinical considerations

“…Metabolic acidosis also stimulates osteoblasts to release prostaglandins, which in turn inhibits osteoblastic activity and stimulates osteoclastic function [99][100][101][102]. Glucocorticoids inhibit the production of prostaglandins by osteoblasts, and this in turn inhibits the acidosis-induced bone resorption [103]. Furthermore, since acid loading in normal animals and humans is associated with hypercalciuria and phosphaturia, it has been suggested that bone is a major site for the extracellular buffering of the retained acid [92,97,[104][105][106][107][108][109].…”

Prevention of colorectal cancer using COX-2 inhibitors: basic science and clinical applications

“…Some environmental factors including heat shock (Hsp90) (28), hypoxia (29), shear stress (30) and ozone stress (31) also have shown to upregulate PGE 2 production. PGE 2 production is inhibited by antioxidant flavonoid (32), gamma-tocopherol (33), vitamin D (34), estrogen (35), dexamethason (36), cortisol (37), or chitosan (38). Food components such as conjugated linoleic acid (39), oleic acid (40), soybean isoflavone (41), tea polyphenols (42), or caffeic acid (43) also depresses PGE 2 production.…”

“…The down regulation of COX-2 expression is largely mediated by the inhibition of MAPK, PKC, AP-1, NF-kappaB and many other intracellular signaling. Caffine (43), alpha-tocopherol (50), ceramide (53), PGJ 2 (54), cortisol (37), dexathmasone (55), PPAR-gamma ligand Accompanying with the up or down regulation of COX-2 expression, the major mechanism(s) and intracellular signaling components involved are provided. ↑ or ↓ denotes activation or inhibition, respectively (56), retinoic acid (57), estradiol (58) or vitamin D (34) depresses COX-2 expression.…”