MECHANISM OF PARATHYROID HORMONE ACTION 579 



The strongest support for the hypothesis that parathyroid hormone 

 induces an increased accumulation of citrate in bone came from the 

 in vivo work of Neuman and co-workers (Neuman et al., 1956; 

 Firschein et al, 1958; Martin et al, 1958) and from the in vitro 

 study bv Lekan et ah ( 1960 ) . However, subsequent work has pro- 

 duced considerable data incompatible with this hypothesis. No 

 evidence of an increase in the accumulation of citrate related to 

 mineral dissolution was found either by chemical analysis (Borle 

 et al., 1960; Raisz et al, 1961) or by radioisotope tracer methods 

 ( Cohn and Forscher, 1961 ) . Although the citrate hypothesis should 

 not be abandoned merely because of contradictory evidence, alter- 

 nate possibilities should certainlv be seriously considered. 



The second hypothesis mentioned related to alterations in the 

 concentration of hydrogen ions. Although the major metabolic end 

 product in bone is an acid, lactic acid, no evidence has been found 

 of an effect of parathvroid honnone on lactate that relates to the 

 dissolving of minerals (Cohn and Forscher, 1962/?; Schartum and 

 Nichols, 1961; Raisz et al, 1961). We proposed that the parathyroid 

 hormone induces a local increase in the amount of available hydro- 

 gen ion bv increasing the production of CO2 (Cohn and Forscher, 

 1962c). The nature of this effect is shown in Table I. The data from 

 the control slices qualitatively indicate hexose monophosphate-shunt 

 activity, which has been verified by calculations based on lactate 

 yields ( Cohn and Forscher, 1962fl ) . 



TABLE I. Efffxt of Parathykoid Extract on ^Mkta holism 

 OF Glucose-C" in Bone 



