Bones formation

The bone pathologist Wolbach (in Wolbach and Bessey, 1942) has dealt with a number of important problems in this field. The following 

Wolhach and Bessey explain rickets as due to deficient absorption of calcium and phosphate and conclude that there is no reason to believe that the cells and matrices concerned in hone growth and maintenance are defective in rickets or are directly acted upon by the vitamin D.  

This generalized conclusion of Wolbach and Bessey, with which the present authors disagree, is based very much upon the work of Shohl and Wolbach (1936). Here, rats at 28 days of age were given a Steenbock-Black diet with varying Ca/P ratio and acidity and were kept on this diet for three weeks. Under these experimental conditions the conclusions are obviously correct. 

Nicolaysen and Jansen (1939) in a series of varied experiments reached the conclusion that vitamin D influences the structure, viz., the matrix of the bones. This work will be reviewed in some detail. Table III, which is condensed from their publication, is instructive as regards the variations in dietary Ca and P. The main argument was that any possible effect of vitamin D on the bones, in addition to the indirect one following defective absorption, could be revealed only if the vitamin D-free and the vitamin D-treated rats received an equal supply of calcium and phosphate into the blood stream. 

It will be seen from Table III that a preparative period was first used, to allow any vitamin D remaining in the body to be metabolized. The two groups were consequently identical at start, in contrast to experiments which start at once, and where traces of vitamin D remaining in the body may affect the results achieved in the weeks following. 

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The vitamin D3 metabolite la,25-dihydroxycholecalciferol is a lifesaving drug in treatment of defective bone formation due to renal failure. Retrosynthetic analysis (E.G. Baggjolint, 1982) revealed the obvious precursors shown below, a (2-cyclohexylideneethyl)diphenylphosphine oxide (A) and an octahydro-4f/-inden-4-one (B), to be connected in a Wittig-Homer reaction (cf. section 1.5). 

The calcification of atherosclerotic plaques may be induced by osteopontin expression, since osteopontin is a protein with a well-characterized role in bone formation and calcification. Vascular smooth muscle cell migration on osteopontin is dq endent on the integrin av 33 and antagonists of av 33 prevent both smooth muscle cell migration and restenosis in some animal model [8]. 

Bone metabolism comprises the processes of bone formation and bone resorption, the key actions by which skeletal mass, structure and quality are accrued and maintained throughout life. In the mature skeleton, anabolic and catabolic actions are mostly balanced due to the tight regulation of the activity of bone forming ( osteoblast) and bone resorbing ( osteoclast) cells through circulating osteotropic hormones and locally active cytokines. 

Osteoblasts are the primary cells responsible for bone formation. They are derived from mesenchymal (stromal) cells that first differentiate into pre-osteoblasts and then into mature, bone matrix producing osteoblasts. Inactivated or resting osteoblasts become lining cells and thus a reservoir for bone forming cells to be activated at the next remodelling cycle. Osteoblasts trapped and embedded in the mineralised matrix are called osteocyts, and are important for many properties of living bone. 

During bone formation, a series of sequential changes occur in cells in the osteoblast lineage, including osteoblast chemotaxis, proliferation and differentiation, which in turn is followed by formation of mineralised bone and cessation of osteoblast activity. The osteoblast changes are preceded by osteoclast apoptosis, which may be dependent on active TGF- 3 released from the resorbed bone. This is followed by chemotactic attraction of osteoblasts or their precursors to the sites of the resorption defect. Chemotactic attraction of osteoblast precursors is likely mediated by local factors produced during the resorption process. 

Bone remodelling, which continues throughout adult life, is necessary for the maintenance of normal bone structure and requires that bone formation and resorption should be balanced. Bone remodelling occurs in focal or discrete packets know as bone multicellular unit (BMU). In this process, both bone formation and resorption occur at the same place so that there is no change in the shape of the bone. After a certain amount of bone is removed as a result of osteoclastic resorption and the osteoclasts have moved away from the site, a reversal phase takes place in which a cement line is laid down. Osteoblasts then synthesize matrix, which becomes mineralised. The BMU remodeling sequence normally takes about 3 months to produce a bone structure unit (Fig. 2). 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

Statins lower plasma cholesterol levels by inhibiting HMG-CoA reductase in the mevalonate pathway (Fig. 4). Some research has shown that certain statins (but not all) stimulate BMP-2 expression in osteoblasts, increase bone formation and mimic N-BP in that they inhibit bone resorption. The use of statins in osteoporosis is presently being investigated. 

Fluorid ions stimulate bone formation by a direct mitogenic effect on osteoblasts mediated via protein kinase activation and other pathways. Further to these cellular effects, fluorides alter hydroxyapatite crystals in the bone matrix. In low doses, fluorides induce lamellar bone, while at higher doses abnormal woven bone with inferior quality is formed. The effect of fluorides on normal and abnormal (e.g. osteoporotic) bone therefore depends on the dose administered. 

Bone Formation The building of new bone through osteoblasts. Bone formation, which is part of the bone remodelling process, includes the synthesis of organic matter (mostly collagen type 1) and subsequent mineralisation. 

Fluoride stimulates bone formation by protein kinase activation mediated effects on osteoblasts. Fluorides have been used in the treatment of osteoporosis, but their anti-fracture effect is not undisputed. 

Osteoporosis is a common condition, in which bone density is decreased as a consequence of an imbalance between bone formation (osteoblast) and bone loss (osteoclast). This leads to fragile bones, which are at an increased risk for fractures. The term porosis means spongy, which describes the large holes seen in these bones. 

Supplementation with high doses of vitamin K1 (1 mg/day for 14 days) or MK-4 (45 mg/day) resulted in decreased levels of undercarboxylated osteocalcin and increase of bone formation markers and in a significant reduction in bone loss, respectively. Using such high doses, any kind of effects besides vitamin K can not yet be ruled out and have to be further elucidated by long term studies. An overview can be found in a review by Palacios [4]. 

Polycystic kidney disease (Polycyst in-1 activates canonical Wnt signaling pathway) Injury-induced renal fibrosis Heart failure Ulcerative colitis Osteoporosis-Pseudoglioma Syndrome (genetic syndrome of defective bone formation) Ulcerative colitis Familial Alzheimer s disease (through interaction with Presenilin-1) Familial Alzheimer s disease (through interaction with Presenilin-1)... 

Osteoporosis is a loss of bone density occurring when the loss of bone substance exceeds the rate of bone formation. Bones become porous, brittle, and fragile. Compression fractures of the vertebrae are common. This disorder occurs most often in postmenopausal women, but can occur in men as well. 

Saad B, Kuhoki M, Matter S, Welti M, Uhlschmid GK, Neuenschwander P, and Suter UW. DegraPol-foam A degradable and highly porous polyestenirethane as a new substrate for bone formation. Artif Organs, 2000, 24, 939-945. 

Studies have demonstrated that treatment with soy or phytoestrogen enriched diets is effective in conserving bone in rodent models of osteoporosis (Anderson and Gamer, 1998 Ishimi et al, 2000 Draper et al, 1997). The mechanism of action of phytoestrogens on bone health is unclear but several mechanisms including inhibition of bone resorption and stimulation of bone formation maybe involved (Fanti etal, 1998 Ishimi e/a/., 1999 Picherit eta/., 2000). Limited data from studies in postmenopausal women have indicated that phytoestrogen supplements have a small, beneficial effect on bone loss in the lumbar spine (Alekel et al, 2000 Potter et al, 1998 Somekawa et al, 2001). 

Morabito et al., 2002 European postmenopause placebo, n = 30 genistein, n = 30 HRT, n = 30 First randomized, double-blind placebo-controlled study. Compared to placebo control, genistein (54 mg/day) consumed for 1 year significantly reduced urinary excretion of bone resorption markers and increased bone formation markers at 6 and 12 months BMD was significantly increased at the femoral neck and lumbar spine plasma genistein concentration was around 1.5 pM. HRT showed similar effects to genistein for BMD. 

Bone maintenance during adulthood is dependent on the equilibrium between bone formation by osteoblast cells and bone resorption by osteoclast cells. Bone loss with age is linked to increased osteoclast activity compared to... 

Table 6.6 Effect of isoflavones in cellular models of bone formation...

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