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1) The document discusses three theories of mineralization: the booster/alkaline phosphatase theory, collagen seeding theory, and matrix vesicle theory.
2) The booster theory proposes that alkaline phosphatase enzymes release inorganic phosphate from organic phosphates, increasing local phosphate concentration and allowing hydroxyapatite crystallization. However, this theory alone does not fully explain the mineralization process.
3) The collagen seeding theory suggests that collagen provides a template for hydroxyapatite crystal formation, with specific amino acid residues acting as sites for calcium and phosphate ion binding and nucleation. This reduces the energy needed for mineralization.
4) Overall the document examines different proposed mechanisms by which mineralization of tissues
1) The document discusses three theories of mineralization: the booster/alkaline phosphatase theory, collagen seeding theory, and matrix vesicle theory.
2) The booster theory proposes that alkaline phosphatase enzymes release inorganic phosphate from organic phosphates, increasing local phosphate concentration and allowing hydroxyapatite crystallization. However, this theory alone does not fully explain the mineralization process.
3) The collagen seeding theory suggests that collagen provides a template for hydroxyapatite crystal formation, with specific amino acid residues acting as sites for calcium and phosphate ion binding and nucleation. This reduces the energy needed for mineralization.
4) Overall the document examines different proposed mechanisms by which mineralization of tissues
1) The document discusses three theories of mineralization: the booster/alkaline phosphatase theory, collagen seeding theory, and matrix vesicle theory.
2) The booster theory proposes that alkaline phosphatase enzymes release inorganic phosphate from organic phosphates, increasing local phosphate concentration and allowing hydroxyapatite crystallization. However, this theory alone does not fully explain the mineralization process.
3) The collagen seeding theory suggests that collagen provides a template for hydroxyapatite crystal formation, with specific amino acid residues acting as sites for calcium and phosphate ion binding and nucleation. This reduces the energy needed for mineralization.
4) Overall the document examines different proposed mechanisms by which mineralization of tissues
Introduction Booster theory Seeding theory Matrix vesicle theory
Mineralization is the process of deposition of
minerals in the organic matrix, which is capable of accepting the minerals. The process of mineralization is an important step in formation of hard tissue of the body. The synthetic cells are responsible for deposition of calcifiable organic matrix with alkaliiie^phosphatase enzyme activity. The mineral component of all hard tissues of the body are chiefly calcium hydroxyapatite crystals which is represented as Ca 10 (PO 4 )6 (OH)2. The biologic apatite crystal has the shape of stubby rhombic prism which varies in size. The crystallites of mesenchymal hard tissues are approximately 100 x 200 x 50 x 50 A dimensions where as hydroxyapatite of enamel forms a considerably larger crystal which is 1,400A long and 800A wide. Although, tissue fluid contains calcium, phosphate and other minerals, spontaneous
crystallization do not take place. This is probably
because of presence of substances inhibiting crystal formation, requirement of energy for mineralization and formation of unstable insufficient amount of crystal, which is unable to cause mineralization. In this situation, mineralization can occur under following circumstances: 1. If there is local increase in concentration of minerals which allows formation of sufficient ionic crystallites required for mineralization. Such process that leads to mineralization is called homogenous nucleation. 2. In presence of a nucleating substance that can act as a template for crystal formation therefore decreasing the energy requirement for mineralization. Nucleating
substance can initiate mineralization even
in the absence of increase in ionic concentration. This is called heterogenous mineralization. 3. The above mechanism will be effective if there are means taremove the inhibitors of mineralization. Once crystal formation is initiated,
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mineralization progresses rapidly, utilizing the
calcifying cartilage contains more alkaline calcium and phosphate ions from the tissue fluid phosphatase than non calcifying cartilage. even at a low concentration of ionic content. Based 2. When slices of cartilage removed from on above observations, theories have been put bone of rachitic animals (affected by forward to explain the process of mineralization. richets) were incubated with calcium and organic phosphates, hydroxyapatite crystals 1. Booster theory or Robinson's alkaline were formed. From this experiment phosphatase theory Robinson came to a conclusion that rachitic This theory is put forward by Robinson in 1923 bone contains alkaline phosphatase which based on some of his experimental evidences. is capable of splitting organic phosphate to He proposed that, alkaline phosphatase enzymes release inorganic phosphates. This present in the organic matrix of calcifying matrix phosphate combines with calcium to produce can hydrolyze organic phosphates such as apatite crystals. pyrophosphate or glucose 1-6 phosphate etc. present in plasma and calcifying tissue fluid, and Robinson's theory of mineralization is not widely release inorganic orthophosphate resulting in local accepted and is criticized for various reasons. increase in phosphate ion concentration. This local 1. Robinson's studies were on rachitic bone increase in ionic component has a boosting effect which is an abnormal tissue. Whether the which would increase the proportion of phosphate result obtained in these studies can be ions sufficient to cause spontaneous precipitation. applied to normal bone is doubtful. The phosphate ions combine with the calcium ions available in tissue fluid to form hydroxyapatite 2. Alkaline phosphatase is observed in other tissues which do not calcify. crystals. According to him initially unstable amorphous calcium phosphate is formed which 3. Inhibitors of certain other enzymes which is then converted into stable calcium do not inhibit alkaline phosphatase activity hydroxyapatite. are found to be preventing mineralization. He has evolved his theory based on his 4. Experimental studies have shown that experiments on alkaline phosphatase. presence of inorganic phosphate and calcium is not sufficient to induce 1. Robinson has observed in his studies that
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mineralization progresses rapidly, utilizing the
calcifying cartilage contains more alkaline calcium and phosphate ions from the tissue fluid phosphatase than non calcifying cartilage. even at a low concentration of ionic content. Based 2. When slices of cartilage removed from on above observations, theories have been put bone of rachitic animals (affected by forward to explain the process of mineralization. richets) were incubated with calcium and organic phosphates, hydroxyapatite crystals 1. Booster theory or Robinson's alkaline were formed. From this experiment phosphatase theory Robinson came to a conclusion that rachitic This theory is put forward by Robinson in 1923 bone contains alkaline phosphatase which based on some of his experimental evidences. is capable of splitting organic phosphate to He proposed that, alkaline phosphatase enzymes release inorganic phosphates. This present in the organic matrix of calcifying matrix phosphate combines with calcium to produce can hydrolyze organic phosphates such as apatite crystals. pyrophosphate or glucose 1-6 phosphate etc. present in plasma and calcifying tissue fluid, and Robinson's theory of mineralization is not widely release inorganic orthophosphate resulting in local accepted and is criticized for various reasons. increase in phosphate ion concentration. This local 1. Robinson's studies were on rachitic bone increase in ionic component has a boosting effect which is an abnormal tissue. Whether the which would increase the proportion of phosphate result obtained in these studies can be ions sufficient to cause spontaneous precipitation. applied to normal bone is doubtful. The phosphate ions combine with the calcium ions available in tissue fluid to form hydroxyapatite 2. Alkaline phosphatase is observed in other tissues which do not calcify. crystals. According to him initially unstable amorphous calcium phosphate is formed which 3. Inhibitors of certain other enzymes which is then converted into stable calcium do not inhibit alkaline phosphatase activity hydroxyapatite. are found to be preventing mineralization. He has evolved his theory based on his 4. Experimental studies have shown that experiments on alkaline phosphatase. presence of inorganic phosphate and calcium is not sufficient to induce 1. Robinson has observed in his studies that
Alkaline Phosphatase
Organic Phosphate
Inorganic Phosphate (Local increase in Phosphate Ions)
Calcium
Hydroxyapatite crystals -4
Amorphous Calcium Phosphate
Alkaline phosphatase and mineralization
mineralization. Rather this also requires
action of some other enzymes. 5. The organic phosphate present in tissue fluid of calcifying matrix is insufficient to produce sufficient inorganic phosphate ions to induce mineralization. Although this theory is been criticized by various authors, the role of alkaline phosphatase in mineralization can't be excluded. Alkaline phosphatase is a group of enzymes that can cleave phosphate ions from organic phosphates at an alkaline pH. This enzyme is found in cell membrane of hard tissue forming cells and in organic matrix of calcifying tissue. In addition to providing phosphate ions, alkaline phosphatase may also be involved in ion transport Neumann has proposed that alkaline phosphatase may be playing important role in mineralization by hydrolyzing pyrophosphate which is a known crystal poison which prevents mineralization, therefore helping in crystal growth. The possible role of alkaline phosphatase in mineralization can be: 1. Hydrolyzing organic phosphates to provide inorganic phosphate ions required for liberalization. 2. Ion transport 3. May help in removing crystal poisons. 2. Collagen seeding theory / nucleation theory / collagen template theory
Some nndeating substances which have spatial
arrangement as that of riydroxyapatite crystals, can act as a mould on template upon which crystals can be laid down. Nucleating substance can initiate nainerahzation even when the ionic concentration is less and also reduce energy required for mineralization. Collagen is the most important seed playing a significant role in mineralization. It is suggested that certain aminoacid residues in collagen with
charged side chains, provide a specific, spatial
arrangement that constitute a template matching for hydroxyapatite. Calcium and phosphate ions present in the extracellular fluid binds to these sites to form hydroxyapatite crystals which grow further by addition of ions. It has been observed that lysine and hydroxylysine groups are specific ion binding sites for phosphate ions, while carboxyl sites associated with aspartic acid and glutamic acid residues act as calcium binding sites to initiate nucleation of hydroxyapatite crystals. The role of collagen in mineralization was suggested based on some experimental evidences. When tendon collagen was added to a solution containing calcium and phosphate, crystal formation was found even when the concentration of ions were lower than what is required for spontaneous mineralization and it was suggested that this had happened due to seeding capacity of collagen. Only the collagen with 64nm periodic banding with three dimensional organization of collagen macromolecule has the capability of functioning as a seed. The gaps between the collagen molecules are filled with proteoglycans which bind to calcium. Calcium is released by enzymatic degradation of proteoglycans. After the removal of proteoglycans, phosphoproteins are attached to the collagen which is broken down by alkaline phosphatase to give rise to phosphate ion. These ions combine to form apatite crystals in the gap zone of collagen. Support for this template theory can be achieved from electron microscopic observation of parallel arrangement of hydroxyapatite crystals and collagen fibers. This theory is'Unable to explain mineralization in all tissued. For e.g.: enamel is a highly mineralized tissue, but does not contain collagen. Mineralization of cartilage begins in ground substance and not in association with collagen.
Therefore possibility of other mechanism should
be considered. Similarly another important question to be answered is why collagen does not initiate mineralization in all connective tissue. Possible explanation for this includea. Collagen in connective tissue that does not calcify, may have spatial arrangement of charges that is different from the collagen in calcifiable tissue therefore unable to act as a suitable template. b. In collagen of soft tissues, the charged site could be protected by some ground substance components which prevent the attachment of the ions to initiate mineralization. These substances are called crystal poison. In calcifiable tissue these substances may be removed by certain mechanism leading to exposure of these charged sites, followed by binding of ions to initiate mineralization. Pyrophosphate is a known crystal poison which is hydrolyzed by alkaline phosphatase enzyme to expose the binding sites. c. Collagen exhibits mtraflbrillar pores through which the calcium and phosphate ions should pass through to reach the nucleating sites located inside the fibrils. The gap between tropocollagen molecules in calcifiable tissues is 0.6nm which is large enough to allow the passage of phosphate ions which are of 0.4nm diameter. The gap in soft tissue collagen is only 0.3nm through which the phosphate ions cannot pass, therefore cannot act as a template for hydroxyapatite crystals. Other nucleating materials 1. Lipids: Lipids have been identified as an important factor associated with mineralization process. Although the exact role of lipids in mineralization is not
identified, experimental evidences suggest
that phospholipids can act as a seed or a template for hydroxyapatite crystal formation. Phospholipids are also capable of stabilizing amorphous calcium phosphate which will later be transformed into hydroxyapatite crystals. Phospholipids are also found in matrix vesicle, which can participate in mineralization. 2. Protein polysaccharides: It has been suggested by some investigators that protein polysaccharides act as a seed for mineralization. Experimental evidences show that proteoglycans and glycosaminoglycans have the capability of binding to calcium ions. Probably these protein polysaccharides regulate the rate of mineralization rather than initiating mineralization. Matrix Vesicle Theory
Matrix vesicles are membrane bound vesicles
isolated from areas of calcification. These structures bud off from the synthetic cells and are released into the organic matrix. It has been observed that the matrix vesicles induces precipitation of hydroxyapatite crystals in vitro from solutions containing calcium and phosphate ions and also are capable of crystal formation even when the solubility of product of calcium and phosphate are as low as 2 millimoles2. The above factors suggest that the matrix vesicles have a capacity to initiate mineralization. Two types of matrix vesicles have been identified Type I matrix vesicle are round or ovoid in shape resembling lysosomes. They contain enzymes such as acid phosphatase and aryl phosphatase. These enzymes can break down proteoglycans and glycosaminoglycans which are inhibitors of mineralization.