Regulation of COX-2 Mediates Acid-Induced Bone Calcium Efflux in Vitro

Krieger, Nancy S.; Frick, Kevin K.; Strutz, Kelly L.; Michalenka, Anne; Bushinsky, David A.

doi:10.1359/jbmr.070316

Cited by 42 publications

(38 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We and others have shown that MET increases osteoclastic bone resorption by a mechanism that is mediated through stimulation of osteoblastic prostaglandin E 2 production (8,18,20,32). This response is initiated by activation of Ca signaling in the osteoblast through a specific proton receptor (9, 15).…”

Section: Discussionmentioning

confidence: 99%

Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone

Krieger

Culbertson

Kyker-Snowman

et al. 2012

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Fibroblast growth factor 23 (FGF23) significantly increases with declining renal function, leading to reduced renal tubular phosphate reabsorption, decreased 1,25-dihydroxyvitamin D, and increased left ventricular hypertrophy. Elevated FGF23 is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the mechanisms by which it is regulated are not clear. Patients with chronic kidney disease have decreased renal acid excretion leading to metabolic acidosis, which has a direct effect on bone cell activity. We hypothesized that metabolic acidosis would directly increase bone cell FGF23 production. Using cultured neonatal mouse calvariae, we found that metabolic acidosis increased medium FGF23 protein levels as well as FGF23 RNA expression at 24 h and 48 h compared with incubation in neutral pH medium. To exclude that the increased FGF23 was secondary to metabolic acidosis-induced release of bone mineral phosphate, we cultured primary calvarial osteoblasts. In these cells, metabolic acidosis increased FGF23 RNA expression at 6 h compared with incubation in neutral pH medium. Thus metabolic acidosis directly increases FGF23 mRNA and protein in mouse bone. If these results are confirmed in humans with chronic kidney disease, therapeutic interventions to mitigate acidosis, such as bicarbonate administration, may also lower levels of FGF23, decrease left ventricular hypertrophy, and perhaps even decrease mortality.osteoblasts; chronic kidney disease THE LEVEL OF THE phosphaturic hormone fibroblast growth factor 23 (FGF23) increases incrementally with declining renal function (29, 33), which results in decreased renal tubule inorganic phosphate (P i ) reabsorption (27, 33), a reduction of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] (27, 33), and subsequent reduced intestinal P i absorption (33). Elevated levels of FGF23 induce left ventricular hypertrophy (6) and are associated with a significant increase in mortality (12).FGF23 is produced in osteocytes and osteoblasts (27); however, the mechanisms by which FGF23 is regulated are not clear. As patients progress from chronic kidney disease (CKD) stage 1 to stage 5, there is a significant incremental increase in FGF23, and patients on dialysis have the highest levels of FGF23 (29). The increase in both P i retention and serum P i during CKD may increase serum FGF23 (31). However, P i may not be a primary regulator of FGF23 since there is little correlation between serum P i and serum FGF23 in patients without CKD (26). 1,25(OH) 2 D has also been shown to directly increase FGF23 production and has been suggested as a "counterregulatory" hormone (24). However, in CKD, where levels of 1,25(OH) 2 D are low (23), 1,25(OH) 2 D is unlikely to be the proximate stimulus for the elevated FGF23 serum levels. Parathyroid hormone (PTH), which is elevated in patients with CKD with secondary hyperparathyroidism (23), stimulates FGF23 expression in osteoblasts (21). However, a large scale study in humans with CKD suggests that levels of FGF23 increase ...

show abstract

Section: Discussionmentioning

confidence: 99%

Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone

Krieger

Culbertson

Kyker-Snowman

et al. 2012

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…1 Whether or not blood pressure responses to alterations in dietary acid (from table salt, NaCl) or base from potassium alkali salts is associated with osteoporosis is unclear. 2 Dietary acid and bone effects Increases in blood acid loads, marked by increased urinary acid excretion, increase calcium efflux from bone in in vitro; 3,4 in human clinical trials, faecal calcium balance was not significantly changed, whereas urine calcium excretion increased, 5,6 leading some authors to suggest that the calcium was coming from bone. 4,6,7 In rats and young men, very high dietary NaCl intake (above the usual diet levels) induce lower blood pH and bicarbonate and higher urinary net acid excretion 8,9 and are associated with increased urinary markers of bone breakdown.…”

Section: Introductionmentioning

confidence: 99%

No evidence that the skeletal non-response to potassium alkali supplements in healthy postmenopausal women depends on blood pressure or sodium chloride intake

et al. 2012

View full text Add to dashboard Cite

BACKGROUND/OBJECTIVES:In vitro studies demonstrate that bone is degraded in an acidic environment due to chemical reactions and through effects on bone cells. Clinical evidence is insufficient to unequivocally resolve whether the diet net acid or base load bone affects breakdown in humans. Increasing dietary salt (sodium chloride, NaCl) mildly increases blood acidity in humans and in rats with increased sensitivity to the blood pressure effects of salt, whereas increased potassium (K) intake can decrease blood pressure. Blood pressure responses to NaCl or K may potentially be a marker for increased bone turnover or lower bone mineral density (BMD) in women at higher risk for osteoporosis and fracture. SUBJECTS/METHODS: We retrospectively analysed data from two data sets (California and NE Scotland) of postmenopausal women (n ¼ 266) enrolled in long-term randomized, placebo-controlled studies of the effects of administration of low-or high-dose dietary K alkali supplementation on bone turnover in relation to sodium or chloride excretion (a marker of dietary salt intake). Mean arterial pressure (MAP) was calculated from blood pressure measures, MAP was divided into tertiles and its influence on the effect of dietary NaCl and K alkali supplementation on deoxypyridinoline markers of bone resorption and BMD by DEXA was tested. Data was analysed for each data set separately and then combined. RESULTS: Percentage change in BMD after 24 months was less for California compared with North East Scotland (hip: À 0.6 ± 2.8% and À 1.5±2.4%, respectively (P ¼ 0.027); spine: À 0.5±3.4% and À 2.6±3.5%, (Po0.001). We found no effect of dietary alkali treatment on BMD change or bone resorption for either centre. Adjusting for the possible calcium-or potassium-lowering effects on blood pressure did not alter the results. CONCLUSIONS: Blood pressure responses to Na, Cl or K intake did not help predict a BMD response to diet alkali therapy.

show abstract

“…Osteoblasts can sense ambient acidity via proton sensor proteins such as OGR-1 (9). Downstream of this initiating event, osteoblastic cycloxygenase (COX-2) mRNA and protein expression increases, leading to stimulated osteoblastic PGE 2 secretion (18). PGE 2 then stimulates in an autocrine fashion, osteoblastic RNA expression of the osteoclast activator, receptor activator of nuclear factor-B ligand (RANKL), while expression of its soluble decoy receptor, osteoprotegerin is unchanged.…”

mentioning

confidence: 99%

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats

Gasser

Hulter

Imboden

et al. 2014

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Gasser JA, Hulter HN, Imboden P, Krapf R. Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats. Am J Physiol Renal Physiol 306: F517-F524, 2014. First published December 19, 2013 doi:10.1152/ajprenal.00494.2013.-Chronic metabolic acidosis (CMA) might result in a decrease in vivo in bone mass based on its reported in vitro inhibition of bone mineralization, bone formation, or stimulation of bone resorption, but such data, in the absence of other disorders, have not been reported. CMA also results in negative nitrogen balance, which might decrease skeletal muscle mass. This study analyzed the net in vivo effects of CMA's cellular and physicochemical processes on bone turnover, trabecular and cortical bone density, and bone microarchitecture using both peripheral quantitative computed tomography and CT. CMA induced by NH4Cl administration (15 mEq/kg body wt/day) in intact and ovariectomized (OVX) rats resulted in stable CMA (mean ⌬ [HCO 3 Ϫ ]p ϭ 10 mmol/l). CMA decreased plasma osteocalcin and increased TRAP5b in intact and OVX animals. CMA decreased total volumetric bone mineral density (vBMD) after 6 and 10 wk (week 10: intact normal ϩ2.1 Ϯ 0.9% vs. intact acidosis Ϫ3.6 Ϯ 1.2%, P Ͻ 0.001), an effect attributable to a decrease in cortical thickness and, thus, cortical bone mass (no significant effect on cancellous vBMD, week 10) attributed to an increase in endosteal bone resorption (nominally increased endosteal circumference). Trabecular bone volume (BV/TV) decreased significantly in both CMA groups at 6 and 10 wk, associated with a decrease in trabecular number. CMA significantly decreased muscle cross-sectional area in the proximal hindlimb at 6 and 10 wk. In conclusion, chronic metabolic acidosis induces a large decrease in cortical bone mass (a prime determinant of bone fragility) in intact and OVX rats and impairs bone microarchitecture characterized by a decrease in trabecular number. osteoporosis; mineral density; metabolic acidosis; overiectomy CHRONIC METABOLIC ACIDOSIS (CMA) is one of the cardinal acidbase disorders, characterized by a primary decrease in body base content and diagnosed clinically by measuring decreased plasma [HCO 3 Ϫ ] and blood pH. The disorder can be caused by increased production or decreased elimination of protons (such as in organic forms of metabolic acidosis or chronic renal failure) or by base losses (such as intestinal bicarbonate loss in diarrhea or bicarbonaturia in proximal tubular acidosis). Metabolic acidosis is regarded as the most common acid-base disorder due to the high worldwide prevalence of chronic diarrheal disease.Bone serves as an important proton buffer in metabolic acidosis and, thus, exhibits a homeostatic role by attenuating the severity of metabolic acidosis. Bone exposed to acidic media in vitro undergoes physicochemical mineral dissolution leading to a fall in mineral sodium, potassium, carbonate, calcium, and phosphate. In this process, calcium released from the bone leads to hypercalciuria, the magnitude of w...

show abstract

Regulation of COX-2 Mediates Acid-Induced Bone Calcium Efflux in Vitro

Cited by 42 publications

References 76 publications

Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone

Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone

No evidence that the skeletal non-response to potassium alkali supplements in healthy postmenopausal women depends on blood pressure or sodium chloride intake

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats

Contact Info

Product

Resources

About