MACROMOLECULAR AGGREGATES IN CALCIFICATION 77 



On the basis of the experimental evidence presented, it would 

 appear that the collagens of all tissues which have fibrils in the 

 specific macromolecular aggregation state characterized by the 640- 

 700-A axial repeat structure should be inherently capable of nucle- 

 ating apatite crystals from metastable calcium phosphate solutions. 

 In the case of the vertebrates, for example, the collagens of all the 

 normall)' unmineralized tissues such as the skin, ligaments, and ten- 

 dons are organized in this fashion, and yet under normal conditions 

 onlv the collagens of skeletal system and tooth are mineralized; it is 

 well known, however, that the former may become mineralized in 

 pathological conditions. To explain these findings, one might sup- 

 pose that bone, cartilage, and tooth collagens are somehow differ- 

 ent from the collagens of non-mineralized connective tissues. This, 

 however, would not explain how ligaments, tendons, or skin col- 

 lagens, for example, may be calcified pathologically. 



On the other hand, it seemed more reasonable to us to postulate 

 that in normally unmineralized tissues there are other substances 

 present which under ordinary circumstances prevent or inhibit 

 calcification (Glimcher ct a/.,' 1957; Glimcher, 1958, 1959). Data 

 indicating that the latter is the correct interpretation come from 

 both in vitro and in vivo studies. In vitro experiments conducted in 

 our laboratories have shown that, whereas native (as opposed to 

 reconstituted ) collagen of tissues such as rat-tail tendon, guinea-pig 

 skin, calfskin, etc., were not able to mineralize, these same collagen 

 fibrils were able to mineralize after appropriate treatment of the 

 tissue by procedures designed to extract and depolymerize certain 

 components of the ground substance (Glimcher, 1958, 1959; Fig. 

 13). This, coupled with the fact that the collagen from these nor- 

 mally unmineralized tissues, when extracted, purified, and recon- 

 stituted into native-type fibrils essentially free of ground substance, 

 is able to mineralize, appears to implicate other inhibitory sub- 

 stances in such tissues. 



Very strong additional support for the hypothesis that native- 

 type collagen fibrils are inherently able to mineralize comes from the 

 studies of Likens et al (1958), Nylen et al. (1958), and Johnson 

 ( 1958 ) , who showed by chemical as well as by electron microscope 

 and x-ray microscope methods that the original collagen fibrils of 

 turkey tendons, and not a special kind of bone collagen, initially 

 calcified in vivo. 



