Vitamin osteoclasts

The steroid hormone 1,25-dihydroxy vitamin D3 (calcitriol) slowly increases both intestinal calcium absorption and bone resorption, and is also stimulated through low calcium levels. In contrast, calcitonin rapidly inhibits osteoclast activity and thus decreases serum calcium levels. Calcitonin is secreted by the clear cells of the thyroid and inhibits osteoclast activity by increasing the intracellular cyclic AMP content via binding to a specific cell surface receptor, thus causing a contraction of the resorbing cell membrane. The biological relevance of calcitonin in human calcium homeostasis is not well established. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Systemic regulators of osteoblast, osteocyte and osteoclast functions, and therefore of bone metabolism. The major bone-seeking hormones are parathyroid hormone (PIH), 1,25-dihydroxy vitamin D3 (calcitriol) and the various ex hormones. 

In bone, three proteins have been described which are vitamin K-dependent, osteocalcin (bone Gla protein), matrix Gla protein (MGP), and protein S. Osteocalcin is synthetized by osteoclasts, regulated by the active form of vitamin D, calcitriol. Its capacity to bind calcium needs a vitamin K-dependent y-carboxylation of three glutamic acid residues. The calcium binding capacity of osteocalcin indicates a possible role in bone mineralization, but its exact function is still unclear. However, it is widely used as a serum marker for bone mineralization. Protein S, mainly a coagulant, is also vitamin-K dependent and synthesized in the liver. Children with... 

It is important to monitor vitamin D therapy aggressively to assure that PTH levels are not oversuppressed. Oversuppression of PTH levels can induce adynamic bone disease, which manifests as decreased osteoblast and osteoclast activity, decreased bone formation, and low bone turnover. 

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

During the 1970s data on the expression of receptors for known stimulators of bone resorption, like PTH and vitamin D3, demonstrated that these receptors were not present on osteoclasts or their precursor cells, but were on osteoblasts (Rodan et al. 1981). Moreover, cellular interactions between stromal/OB cells... 

The receptor for RANKL is RANK, also known as ODAR (Anderson et al. 1997 Hsu et al. 1999). RANK is expressed in osteoclast precursors, mature osteoclasts, condrocytes, fibroblasts, and immune system cells (Anderson et al. 1997 Hsu et al. 1999). The binding of RANKL with RANK on preosteoclasts initiates the OCS and the activation of osteoclasts (Anderson et al. 1997 Hsu et al. 1999 Nakagawa et al. 1998). RANK-deficient mice display a phenotype characterized by osteopetrosis and several defects in the immune system similar to that observed in RANKL-deficient mice (Dougall et al. 1999). Consistent with this hypothesis, RANK-deficient mice are resistant to bone resorption induced by TNF-a, IL-l/J, or vitamin D3 (Li et al. 2000). In agreement with this, mice deficient in molecules implied in the transduction pathway from RANK like TRAF-6 or NF-/c Bl/NK-/c B2 also show an osteopetrotic phenotype,... 

As we age, the activity of osteoclasts tends to outrun that of osteoblasts, leading to gradual loss of bone and increasing susceptibility to bone fracture. In the elderly, a hip fracture has about the same mortality rate as a heart attack. Crush fractures of vertebrae lead to an abnormal curvature of the spine and an inability to stand up straight. So, exercise and get enough calcium and vitamin D in your diet. 

The polypeptide parathormone is released from the parathyroid glands when plasma Ca + level falls. It stimulates osteoclasts to increase bone resorption in the kidneys, it promotes calcium reabsorption, while phosphate excretion is enhanced. As blood phosphate concentration diminishes, the tendency of calcium to precipitate as bone mineral decreases. By stimulating the formation of vit D hormone, parathormone has an indirect effect on the enteral uptake of Ca + and phosphate. In parathormone deficiency, vitamin D can be used as a substitute that unlike parathormone, is effective orally. 

The bisphosphonates are all analogues of pyrophosphate. They inhibit osteoclast resorption of bone and they are able to inhibit the formation and dissolution of hydroxyapatite crystals, however their exact mechanism is not well understood. Other effects which have relevance for bone homeostasis include inhibition of the activities of PTH, prostaglandins and 1,25-dihydroxy vitamin D. Bisphosphonates bind to bone with high affinity. They have therefore a duration of action that continues long after their use has been stopped. 

Cholecalciferol (D3) and its active form 1,25-di-hydroxycholecalciferol are only to a certain extend vitamins because they can be synthesized by the human body. However deficiencies resulting in rickets in children and osteomalacia in adults do exist. Cholecalciferol can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize ergosterol, which is converted to vitamin D2 (ergocalciferol) by ultraviolet light. Vitamin D2 may be less active in humans. Vitamin D promotes uptake of calcium and phosphate in the intestine and it stimulates osteoclasts to break down hydroxyapatite and release calcium into blood. Vitamin D is discussed in more detail in Chapter 24, Section V.a. 

Mechanism of Action An antibiotic that forms complexes with DNA, inhibiting DNA-directed RNA synthesis. May inhibit parathyroid hormone effect on osteoclasts and inhibit bone resorption. TherapeuticEffect Lowers serum calcium and phosphate levels. Blocks hypercalcemic action of vitamin Dand action of parathyroid hormone. Decreases serum calcium. 

Three hormones serve as the principal regulators of calcium and phosphate homeostasis parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and the steroid vitamin D (Figure 42-2). Vitamin D is a prohormone rather than a true hormone, because it must be further metabolized to gain biologic activity. PTH stimulates the production of the active metabolite of vitamin D, l,25(OH)2D. l,25(OH)2D, on the other hand, suppresses the production of PTH. l,25(OH)2D stimulates the intestinal absorption of calcium and phosphate. l,25(OH)2D and PTH promote both bone formation and resorption in part by stimulating the proliferation and differentiation of osteoblasts and osteoclasts. Both... 

Certain human populations depend on dietary sources of vitamin D because of insufficient biosynthesis of the vitamin due to inadequate skin exposure to sunlight. The classic symptoms of vitamin D deficiency are rickets in children and osteomalacia in adults. 25-Hydroxyvitamin D3 is the major circulating metabolite in the blood, but the hormonally active form of the vitamin is 1,25-dihydroxyvitamin D3. The latter metabolite stimulates the intestine to absorb calcium and phosphate by two independent mechanisms and acts with parathyroid hormone to mobilize calcium, accompanied by phosphate, from the bone fluid compartment into the bloodstream. 1,25-dihydroxyvitamin D 3 is also involved in the formation of osteoclasts—giant cells that are solely responsible for the resorption of bone matrix (33). Resorption is an essential process for the development, growth, maintenance, and repair of bone. 

Adebanjo OA, Moonga BS, Haddad JG, Huang CL-H, Zaidi, M. 1998b.. A possible new role for vitamin D-binding protein in osteoclast control. Inhibition of Ca2+ sensing at low physiological concentrations. Biochem Biophys Res Commun249 668-671. 

Bone is a relatively dynamic organ that undergoes significant turnover that is, hone resorption and deposition it is broken down hy osteoclasts and rebuilt by osteoblasts. Besides an adequate supply of calcium, a close cooperation is required between these two types of cell. Complex signalling pathways achieve proper rates of growth and differentiation these pathways include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids and calcitonin, as well as several cytokines. 

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