Metabolic, but not respiratory, acidosis increases bone PGE₂levels and calcium release

Abstract

. Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release. Am J Physiol Renal Physiol 281: F1058-F1066, 2001. First published July 12, 2001; 10.1152/ajprenal.00355.2001A decrease in blood pH may be due to either a reduction in bicarbonate concentration ([HCO 3 Ϫ ]; metabolic acidosis) or to an increase in PCO2 (respiratory acidosis). In mammals, metabolic, but not respiratory, acidosis increases urine calcium excretion without altering intestinal calcium absorption, indicating that the additional urinary calcium is derived from bone. In cultured bone, chronic metabolic, but not respiratory, acidosis increases net calcium efflux (JCa), decreases osteoblastic collagen synthesis, and increases osteoclastic bone resorption. Metabolic acidosis increases bone PGE2 production, which is correlated with JCa, and inhibition of PGE2 production inhibits this acid-induced JCa. Given the marked differences in the osseous response to metabolic and respiratory acidosis, we hypothesized that incubation of neonatal mouse calvariae in medium simulating respiratory acidosis would not increase medium PGE 2 levels, as observed during metabolic acidosis. To test this hypothesis, we determined medium PGE2 levels and JCa from calvariae incubated at pH ϳ7.1 to model either metabolic (Met; [HCO 3 Ϫ ] ϳ11 mM) or respiratory (Resp; PCO2 ϳ83 Torr) acidosis, or at pH ϳ7.5 as a control (Ntl). We found that after 24-48 and 48-51 h in culture, periods when cell-mediated JCa predominates, medium PGE2 levels and JCa were increased with Met, but not Resp, compared with Ntl, and there was a direct correlation between medium PGE 2 levels and JCa. Thus metabolic, but not respiratory, acidosis induces the release of bone PGE2, which mediates JCa from bone. calvariae; osteoblasts; protons; pH IN HUMANS AND EXPERIMENTAL ANIMALS, chronic metabolic acidosis, a decrease in systemic pH induced by a decrease in serum bicarbonate concentration ([HCO 3 Ϫ ]), increases urine calcium excretion (15, 49, 51) without increasing intestinal calcium absorption (50, 51), resulting in a negative calcium balance (15,50,51). Because Ͼ98% of total body calcium is contained within the bone mineral (83), this negative calcium balance strongly implies a loss of bone calcium. Indeed, in humans dietary intake of acid precursors causes an apparent decrease in bone mineral content, which is reversed by the provision of alkali (50, 67).In contrast, chronic respiratory acidosis, a decrease in systemic pH induced by an increase in PCO 2 , appears to have little (30) or no (48, 65, 66) effect on urine calcium excretion. Clearly, any effect on urine calcium excretion is far less than that induced by metabolic acidosis (30). Serum calcium may increase slightly during respiratory acidosis (48). The lack of an appreciable change in urine calcium excretion during respiratory, compared with metabolic, acidosis suggests a marked difference in the osseous response to these two types of acidosis (10).We have extensively compared the response of cultured bone...

Cortisol Inhibits Acid-Induced Bone Resorption In Vitro

“…Acid medium stimulates osteoblastic PGE 2 production, which mediates the subsequent stimulation of osteoclastic bone resorption (12)(13)(14)35). Cortisol has previously been shown to inhibit prostaglandin production (36) as well as hormonal stimulation of the rate-limiting enzyme that converts arachidonic acid to PGE 2 (prostaglandin G/H synthase, PGHS-2) in neonatal mouse calvariae (37).…”

“…With prolonged incubation in acidic medium, there is decreased osteoblastic bone formation and increased osteoclastic resorption (9,10), all of which contribute to a net efflux of calcium from bone (6,11). This cell-mediated resorption appears due to increased osteoblastic prostaglandin E 2 (PGE 2 ) synthesis, leading to a suppression of osteoblastic bone formation and subsequent stimulation of osteoclastic bone resorption (12)(13)(14).…”

Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts

“…Resp acidosis does not alter osteoclastic ␤-glucuronidase release, osteoblastic collagen synthesis, or alkaline phosphatase activity as does Met acidosis (7). Medium PGE 2 levels and net calcium efflux from bone were increased in parallel with Met, but not Resp, acidosis (20).…”

“…To model Met acidosis, the medium pH was lowered to ϳ7.10 by the addition of 1 ml of 2.4 M HCl to 100 ml Ntl medium to lower the medium [HCO 3 Ϫ ] as previously reported (5,7,10,13,15,47,48). To model Resp acidosis, the pH was lowered to ϳ7.10 by increasing the PCO 2 of the medium through gentle bubbling with 10% CO2 in air (AirGas) as previously reported (5,7,15,20,32).…”

“…Met acidosis increases osteoblastic expression of cyclooxygenase 2 (COX-2) (47) and receptor activator of NF-B ligand (RANKL) (33,35), the latter which interacts with its osteoclastic receptor RANK to stimulate bone resorption. Met acidosis also alters osteoblastic extracellular matrix by decreasing expression of type 1 collagen (7,9,19,20,34,48), osteopontin, and matrix gla protein (31,32), which limits bone formation, and increases secretion of ␤-glucuronidase by osteoclasts (7,19,48), which stimulates bone resorption.…”