The authors have no conflict of interest
Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism†
Article first published online: 1 JUL 2003
Copyright © 2003 ASBMR
Journal of Bone and Mineral Research
Volume 18, Issue 7, pages 1317–1325, July 2003
How to Cite
Frick, K. K. and Bushinsky, D. A. (2003), Metabolic Acidosis Stimulates RANKL RNA Expression in Bone Through a Cyclo-oxygenase-Dependent Mechanism. J Bone Miner Res, 18: 1317–1325. doi: 10.1359/jbmr.2003.18.7.1317
- Issue published online: 2 DEC 2009
- Article first published online: 1 JUL 2003
- Manuscript Accepted: 24 JAN 2003
- Manuscript Revised: 6 DEC 2002
- Manuscript Received: 1 OCT 2002
Metabolic acidosis inhibits osteoblastic bone formation and stimulates osteoclastic resorption. To determine whether acidosis alters expression of RNA for the osteoclastic differentiation factor RANKL, mouse calvariae were incubated in neutral or physiologically acidic media. Acidosis resulted in a significant cyclo-oxygenase-dependent increase in RANKL RNA levels, which would be expected to induce the associated increase in bone resorption.
Introduction: Metabolic acidosis increases net calcium efflux from bone, initially through physicochemical mechanisms and later through predominantly cell-mediated mechanisms. Acidosis decreases osteoblastic bone formation and increases osteoclastic resorption. The growth and maturation of osteoclasts, derived from hematopoietic precursors in the monocyte/macrophage lineage, are dependent on the interplay of a number of factors. Commitment of pre-osteoclasts to osteoclasts is induced by the interaction of the osteoclastic cell-surface receptor RANK with a ligand expressed by osteoblasts, RANKL. The RANK/RANKL interaction not only initiates a differentiation cascade that culminates in mature bone-resorbing osteoclasts but also increases osteoclastic resorptive capacity and survival.
Methods: To test the hypothesis that metabolic acidosis increases expression of RANKL, we cultured neonatal mouse calvariae in acidic (initial medium pH ∼7.1 and [HCO3−] ∼11 mM) or neutral (initial medium pH ∼7.5 and [HCO3−] ∼25 mM) medium for 24 and 48 h. We determined the relative expression of RANKL RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitated the expression by Northern analysis.
Results: In this model of metabolic acidosis, there was significantly increased expression of RANKL RNA at both 24 (2-fold) and 48 h (5-fold) compared with respective controls. Net calcium efflux from bone was also increased in acidic medium compared with control medium. At 48 h, net calcium efflux correlated directly with RANKL expression (r = 0.77, n = 15, p < 0.001). Inhibition of prostaglandin synthesis with indomethacin blocked the acid-induced increase in RANKL RNA as well as the increased calcium efflux.
Conclusions: Metabolic acidosis induces osteoblastic prostaglandin synthesis, followed by autocrine or paracrine induction of RANKL. This increase in RANKL would be expected to augment osteoclastic bone resorption and help explain the increase in cell-mediated net calcium efflux.