558 G. NICHOLS, jr. 



their imagination, skill, and hard work little would ha\'e been ac- 

 complished. 



Either modification or disorganization-and-remo\'al of the complex 

 of heavih' calcified collagen, ground substance, and cells which we 

 call bone is required for the successful accomplishment of several 

 phenomena of great import in the life of many species. One or both 

 are required for the maintenance of calcium and phosphorus con- 

 centrations in the circulating fluids, for the remodeling of the skeletal 

 structures during growth, for the internal remodeling of compact 

 bone, and for the removal of bone irretrievablv damaged by disease 

 or trauma. The first of these phenomena, at least in theory, need 

 involve onh' a mechanism for the mobilization and remo\'al of some 

 of the mineral phase of the tissue. On the other hand, the last three 

 involve the total simultaneous removal of three separate t\"pes of 

 extracellular material — mineral salts, collagen, and the polysaccha- 

 rides of the ground substance — as well as the cells themselves. More- 

 over, it seems likeh' that, with the possible exception of the removal 

 of dead bone, the mechanisms for bone resorption are endogenous 

 to the bone itself and are lodged in some fashion in the cellular 

 elements of the tissue. In other words, chemical mechanisms must 

 be potentiallv present in the cells of living bone for ( 1 ) the solubili- 

 zation of the mineral phase, (2) the destruction or solubilization of 

 collagen, (3) the removal of polysaccharides, and (4) the destruc- 

 tion and remoxal of bone cells. 



In vitro svstems offer the best chance to obtain direct e\idence 

 for such local chemical mechanisms and to examine their nature 

 and control. The success of our attempts to measure the over-all 

 metabolism of living bone fragments in vitro (Borle, Nichols, and 

 Karnovsky, I960; Borle, Nichols, and Nichols, 1960/?) suggested that 

 such systems were feasible and opened a wav to examine each of 

 these four postulated mechanisms. So far, we have explored the first 

 in some detail and have \'erv recentlv begun work on the second. 

 The last two remain imtouched b\' us although others have found 

 evidence suggesting their existence (Bollett, 1962; Fell et ah, 1962). 



Our first experiments were stimulated bv an interest in the mobili- 

 zation of bone salts to maintain the calcium ion concentration in 

 the extracellular fluid. At that time Neuman and collaborators ( Neu- 



