218 G. Nichols, JR. 



Once inside, substrates can be used for a variety of purposes. Glucose and amino- 

 acids have both been shown to serve as fuel for energy producing systems. These, we 

 know, follow the same general scheme in bone as in all tissues — hexoses are degraded 

 in step-wise fashion through the glycolytic pathway to pyruvate. Unlike most tissues, 

 however, the majority of this pyruvate is used in bone to form lactate which is 

 excreted from the cell while only about 10 per cent goes on through the tricarboxylic 

 acid cycle. Thus ATP is produced both anaerobically and aerobically (presumably 

 via mitochondrial oxidative phosphorylation) with the release of chiefly "non- 

 volatile" acid end products — lactic and citric acids — which seem likely to play an 

 important role in bone resorption and calcium homeostasis (Nichols, 1963). 



Amino-acids (Flanagan and Nichols, 1962), concentrated in the cell sap by 

 active transport or synthesized intracellularly from carbohydrate precursors (Flana- 

 gan and Nichols, 1964), are used chiefly in the biosynthesis of proteins. In the dia- 

 gram a single common pathway for protein synthesis is shown because only one is 

 believed to exist — the particular amino-acid sequence characteristic of each protein 

 being determined by the particular messenger RNA upon which the polysome which 

 makes it is assembled. The messenger RNA is represented as being derived from the 

 nucleus — a notion whose application to bone cells is supported by recent experi- 

 ments (Simmons and Nichols, 1964; Steinberg and Nichols, unpublished studies). 

 Current belief, of course, holds that at least part of this nuclear RNA is a com- 

 plementary copy of a section of a DNA chain in which is encoded the necessary 

 information for specifying the structure of the protein whose synthesis is guided by 

 the RNA "messenger". The arrow representing the transfer of messenger RNA to the 

 polysomes has been made double to remind us that the differences between the 

 systems which make collagen on the one hand and coUagenase on the other probably 

 lie at this "informational" level. 



One other point about these 2 bone cell products is shown. Both are thought to 

 be stored in membrane bounded vacuoles before being released into the extra- 

 cellular space (Porter, 1964; Woods and Nichols, in press). Although the 

 apparent intermittency of collagen deposition under certain conditions (tanzer, 

 1964) suggests that this feature might be important in the control of new bone matrix 

 synthesis, no evidence on this point is yet available. Fiowever, recent evidence 

 (Asher and Nichols, 1965) suggests that the storage of coUagenase in such intra- 

 cellular bodies may offer an important means of controlling bone resorption. 



Having refreshed our memory regarding the main features of bone cells and 

 their physiology we can examine these schemes and current biochemical knowledge 

 for likely hormone targets. Three general areas where hormones might act form the 

 3 main headings of Fig. 2. Possible mechanisms of action at the molecular level under 

 each heading are listed below it — predictions which are based on what is commonly 

 known about the biochemistry, biophysics, and fine structure of cells. The fact that 

 these mechanisms occur in more than one area is indicated by repetitions and the 

 arrows between headings. 



The extraordinary prominence of membranes in the structure of all cells suggests 

 that the rates of cellular metabolic processes could readily be controlled by regulating 

 the passage of materials across these boundaries, as indicated by the first heading. 

 Three general modes of transfer across membranes are known: 1) diffusion whose rate 

 depends on the physical characteristics of the membrane and an electrochemical 



