Osteoid tissue

Fig. 9.4 Osteoblast secretion and matrix vesicle formation. The outer surface of all bones is covered by fibroblast-like cells that differentiate into pre-osteoblasts that secrete osteoid matrix to remodel the surface as necessary. The surface osteoblasts extend into the osteoid tissue by long processes that attach to osteocytes (fully differentiated, nondividing osteoblasts) within the bone. Changes in the environment may be sensed by the osteocytes, which transmit them as remodeling signals to the osteoblasts. The osteoid matrix is filled with many small membrane-covered matrix vesicles containing various amounts of precipitated basic calcium phosphate (white circles) (Modified from Fig. 22-52 in The Molecular Biology of the Cell. B. Alberts et al., 4th Ed. 2002. Garland Science, Taylor Francis Group, New York)...

Vitamin D is a fat soluble vitamin related to cholesterol. In the skin, sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol. 7-Dehydrocholesterol spontaneously isomerizes to cholecalciferol (vitamin D3), which is oxidized in the liver to 25-hydroxy cholecalciferol and, under the influence of PTH in the kidney, to 1,25-dihy-droxy cholecalciferol (calcitriol), the active form of vitamin D. Vitamin D induces the expression of calcium ion transport proteins (calbindins) in intestinal epithelium, osteoclasts, and osteoblasts. Calbindins and transient receptor potential channels (TRPV) are responsible for the uptake of calcium from the diet. In children, the absence of sunlight provokes a deficiency of vitamin D, causing an absence of calbindins and inadequate blood calcium levels. Osteoid tissue cannot calcify, causing skeletal deformities (rickets). In the elderly, there is a loss of intestinal TRPV receptors and decreased calbindin expression by vitamin D. In both cases, the resultant low blood calcium levels cause poor mineralization during bone remodeling (osteomalacia). Rickets is the childhood expression of osteomalacia. Osteoclast activity is normal but the bone does not properly mineralize. In osteoporosis, the bone is properly mineralized but osteoclasts are overly active. 

In this connection a short discussion of osteoid tissue is relevant. Actually, the occurrence of osteoid is not associated with vitamin D deficiency only, in spite of the fact that it is best known in this connection and is used by the morphologists as a criterion of rickets. Korenchevsky (1922) described a rich occurrence of osteoid in rats given a diet liberal in vitamin D but poor in calcium. In renal rickets where there is no vitamin D deficiency but an acidosis, osteoid appears very clearly. Follis (1950) described abundant osteoid in hypervitaminosis D. In elderly people osteoid appears to be useful in separating osteoporosis from osteomalacia. 

Figure 1. The cellular activity during bone remodelling. At the tip (cutting cone) multi-nucleated osteoclasts (OCLs) excavate the mineralised bone tissue. At some distance, after the resting zone, osteoblasts (OBLs) refill the tunnel with (osteoid) that is subsequently mineralised. Osteocytes (OCYs) are former osteoblasts that were entombed within the bone matrix, but remained connected to the bone surface by numerous long slender protrusions (not visible). Courtesy R. Schenk.

First described in 1979 as secreted phosphoprotein 1 (Senger et al., 1979), OPN has a shorter history but shares with MIF some of its mystique. The name osteopontin derives from the fact that the protein was found to be present in the bone, and as it is localized in the osteoid matrix, it is believed that it can form a bridge between bone and the adjacent cellular tissues (Oldberg et ah, 1986). 

Intramembranous ossification is responsible for most of the mineralization of the skull, including the maxilla and mandible. It begins with the differentiation and activation of osteoblasts from fibroblast-related precursors within a region of connective tissue that demarcates where the bone will develop. The osteoblasts secrete a nonmineralized protein-rich (osteoid) matrix and, as they move away, the matrix mineralizes (Fig. 9.3a). The periosteum remains uncalcified and contains latent and undifferentiated osteoblasts for bone remodeling. Odontoblasts (Ob) and cementoblasts secrete an osteoid-like matrix similar to that of intramembraneous ossification. 

Skeletal tissue mineralization (bone formation) is initiated by osteoblasts, which secrete the osteoid matrix (Fig. 9.4). They express type I procollagen in secretory vesicles together with matrix vesicles that pinch off from the membrane. The matrix vesicles are pushed away from the cell surface, possibly by the flow of fluid containing calcium and phosphate ions that are also transported through the cell from the extracellular fluid on the outer surface. Collagen fibers develop further away from the cell surface than from fibroblasts. 

A physiologic phosphate concentration is required for bone mineralization. Lowering the concentration prevents mineralization, but raising it does not ensure precipitation because pyrophosphate is present to inhibit precipitation. The concentration of PPi in cartilage and bone is controlled by three enzymes, two on the outer surface of matrix vesicles (Fig. 9.5b). One is tissue-nonspecific alkaline phosphatase (TNAP), which decreases stromal pyrophosphate and the other is NTP-PPi hydrolase (also called plasma cell membrane glycoprotein-1), which increases it. The progressive ankylosis gene product (ANK protein) is expressed by osteoblasts to add to the pyrophosphate of the osteoid matrix from osteoblast cytosol. 

Osteoblasts secrete osteoid, a matrix rich in type I collagen fibers and vesicles. Precipitation of calcium phosphate is inhibited by a high concentration of pyrophosphate in stromal interstitial fluids, and a high concentration also of albumin and citrate in blood plasma. Pyrophosphate is derived from (1) transport out of the cytosol, and (2) synthesis from nucleoside triphosphates in the stromal interstitial fluid that permeates the osteoid matrix. Precipitation occurs only when calcium and phosphate ions are taken up into vesicles whose inner membrane is composed of phosphatidylserine. The high concentration of calcium and phosphate ions in the vesicle is mediated by annexin and type HI Pi Na-dependent transporters. This overwhelms the pyrophosphate and nucleation occurs. As the precipitate grows and ruptures the membrane, tissue-nonspecific alkaline phosphatase is activated to remove pyrophosphate from the osteoid matrix fluid so that calcium phosphate precipitates around phosphorylated serine residues within the collagen fibers. 

Microscopically, OS is composed of anaplastic pleomorphic cells with a morphologic spectrum including spindle, round, ovoid, epithelioid, plasmacytoid, clear, and multinucleated cells. Usually more than one cell type is present in individual OS. Osteoid is required for the diagnosis. Variable bone formation, cartilage, and fibrous tissue may also be encountered. Histologic subtypes of conventional OS include osteoblastic, chondroblastic, and fibroblastic patterns. Ultrastructural studies have also demonstrated multiple cell types including osteoblastic, osteoclastic, chondroblastic, and fibroblastic features. ... 

The fact that a single BMP/OP initiates bone formation by induction does not preclude the requirement for interactions with other morphogens deployed synchronously and synergistically during the cascade of bone formation by induction, which may proceed via the combined action of several BM Ps/OPs resident within the natural milieu of the extracellular matrix of bone [15, 25]. Partially purified preparations from bone matrix are known to contain, in addition to specific BM Ps/OPs, several other proteins and some as yet poorly characterized mitogens [28]. Indeed, 90 days after implantation, regenerated tissue induced by 2.5 mg of partially purified BM Ps/OPs combined with gamma-irradiated matrix, had mineralized bone and osteoid volumes comparable to specimens induced by 0.5-mg hOP-1 devices (Fig. 1) [15]. 

Fig. 2 Photomicrographs of tissue induction and morphogenesis in bioptic material 90 days after implantation of naturally derived BMPs/OPs purified from bovine bone matrix in human mandibular defects, (a) Trabeculae of newly formed mineralized bone covered by continuous osteoid seams within highly vascular stroma, (b) and (c) High-power views showing...

Fig. 3 Photomicrographs of periodontal tissue engineering and morphogenesis by BMPs/OPs in the primate Papio ursinus. (a and b) Furcation defects 60 days after implantation of 250 pg of naturally derived BMPs/OPs showing regeneration ofcementum, periodontal ligament fibers, and mineralized alveolar bone surfaced by continuous osteoid seams, (c and d)...

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