Cellular mechanisms of bone resorption induced by metabolic acidosis.
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 induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In bone, prostaglandins (PGs) are important mediators of bone resorption and we have recently determined that acid-induced bone resorption is mediated by PGs. Utilizing neonatal mouse calvariae in culture, we found that decreasing pH by a reduction in bicarbonate concentration, a model of metabolic acidosis, induced an increase in net calcium efflux and in medium prostaglandin E2 (PGE2) levels, both of which were inhibited in the presence of indomethacin. There was a direct correlation between calcium flux and medium PGE2. If pH is lowered to a comparable degree by an increase in pCO2 to model respiratory acidosis, there was no significant stimulation of net calcium efflux from the calvariae and no stimulation of PGE2 production. We have also shown that metabolic acidosis alters osteoblastic expression of a specific osteoclastogenic factor, RANKL, and this response is also PG dependent. Incubation of calvariae in acid medium stimulated expression of RANKL RNA in parallel with the increased calcium flux. Both responses were inhibited in the presence of indomethacin. Thus metabolic, but not respiratory, acidosis induces production of bone PGE2, which mediates acid-induced bone resorption.
Krieger
Nancy S
NS
Nephrology Unit, Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. Nancy_Krieger@urmc.rochester.edu
Bushinsky
David A
DA
Frick
Kevin K
KK
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D051379:Mice; D011453:Prostaglandins / Q000502:physiology*
D011453:Prostaglandins; D002118:Calcium