pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis

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Abstract
We examined the effects of HCO3− and CO2 acidosis on osteoclast-mediated Ca2+ release from 3-day cultures of neonatal mouse calvaria. Ca2+ release was minimal above pH 7.2 in control cultures but was stimulated strongly by the addition of small amounts of H+ to culture medium (HCO3− acidosis). For example, addition of 4 meq/l H+ reduced pH from 7.12 to 7.03 and increased Ca2+ release 3.8-fold. The largest stimulatory effects (8- to 11-fold), observed with 15–16 meq/l added H+, were comparable to the maximal Ca2+ release elicited by 1,25-dihydroxyvitamin D3[1,25(OH)2D3; 10 nM], parathyroid hormone (10 nM), or prostaglandin E2 (1 μM); the action of these osteolytic agents was attenuated strongly when ambient pH was increased from ∼7.1 to ∼7.3. CO2 acidosis was a less effective stimulator of Ca2+ release than HCO3−acidosis over a similar pH range. Ca2+ release stimulated by HCO3− acidosis was almost completely blocked by salmon calcitonin (20 ng/ml), implying osteoclast involvement. In whole mount preparations of control half-calvaria, ∼400 inactive osteoclast-like multinucleate cells were present; in calvaria exposed to HCO3− acidosis and to the other osteolytic agents studied, extensive osteoclastic resorption, with perforation of bones, was visible. HCO3− acidosis, however, reduced numbers of osteoclast-like cells by ∼50%, whereas 1,25(OH)2D3 treatment caused increases of ∼75%. The results suggest that HCO3− acidosis stimulates resorption by activating mature osteoclasts already present in calvarial bones, rather than by inducing formation of new osteoclasts, and provide further support for the critical role of acid-base balance in controlling osteoclast function.