Effect on osteoclasts

An in vitro cell model resembles the remodeling process of osteoclastic bone resorption followed by osteoblastic bone formation investigate the influence of lead on the communication between these cells determine if lead in the medium (i.e. extracellular fluid) or in the matrix (i.e. in the bone) has different effects on osteoclasts and osteoblasts... 

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. 

The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42-4). Etidronate, pamidronate, and alendronate have now been joined by risedronate, tiludronate, ibandronate, and zoledronate for clinical use. The bisphosphonates owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. They localize to regions of bone resorption and so exert their greatest effects on osteoclasts. However, the exact mechanism by which they selectively inhibit bone resorption is not clear. 

FIG. 15 Effect of lycopene on resorption of the calcium phosphate substrate coating of osteologic multitest slides in the presence of osteoclasts (Rao et al., 2003). (Lycopene I -Effect on osteoclasts Lycopene inhibits basal and parathyroid hormone-stimulated osteoclast formation and mineral resorption mediated by reactive oxygen species in ray bone marrow cultures. Reprint from Journal of Medicinal Food. 2003 6, pp. 69-78 by permission of Mary Ann Liebert, Inc., Publishers.)... 

The osteoblast and osteoclast can be considered to be the basic multicellular units of bone. The osteoblast plays an important role in mediating local osteoclast activity through the release of chemical messengers. The principal factors responsible for stimulation of bone resorption, such as parathyroid hormone, interleukin-1 (Il-l), and IL-6, have minimal effects on osteoclasts, but osteoblasts have receptors for these substances. 

Although bisphosphonates prevent hydroxyapatite dissolution, their antiresorptive action is due to direct inhibitory effects on osteoclasts rather than strictly physiochemical effects. The antiresorptive activity apparently involves two primary mechanisms osteoclast apoptosis and inhibition of components of the cholesterol biosynthetic pathway. 

To clarify the mechanism of action of these diterpenoids on bone resorption, their effect on osteoclast-like cell formation was tested according to the method reported by Takahashi et al.[34]. As a result, both compounds dose-dependently inhibited PTH-induced tartrate resistant acid phosphatase-positive MNC formation. Especially, SDC showed complete inhbition at concentration over 0.1 pM. Next, the effect of SDB and SDC on resorbing activity of osteoclasts (pit forming activity of osteoclast-like cells) was assayed according to the method of Tamura et al. [35]. As indicated in Table 8, both compounds inhibited the pit-formation when osteoclasts obtained by the co-culture were placed on dentine slice in the presence of these compounds. Therefore, the inhibitory effect of... 

An inhibitor of osteoclast differentiation and / or function is expected to be useful for treatment of bone lytic diseases such as osteoporosis, rheumatoid arthritis, and tumor metastasis into bone. Paenol inhibits RANKL-induced osteoclastogenesis by inhibiting ERK, p38, and NF-kB pathway (Tsai et ah, 2008). S)unbioimine (Fig. 32.2A) from the symbiotic marine dinoflagellate Symbiodinium sp. exhibits inhibitory effect on osteoclast differentiation (Kita et ah, 2004). 

Some herbs are used in bone fracture treatment as well as osteoporosis. The studies of Sun et al. 2002 and Jeong et al. 2005 [4, 5] showed that Gu-Sui-Bu has potential effects on primary and secondary bone cells culture. The herbal extract enhanced proliferation and differentiation of bone cell in the studies. On the other hand, the crude extract has been proven possessing inhibition effect on osteoclast obtained from fetal mouse long bone [6]. 

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... 

GAO Y H and YAMAGUCHi M (1999a) Inhibitory effect of genistein on osteoclast-like cell formation in mouse marrow cultures. Biochem Pharmacol 58, 767-72. 

Calcitonin. This hormone, which is also secreted from the thyroid gland, is synthesized by the parafollicular cells (C cells) located between the follicles. The primary effect of calcitonin is to decrease the blood levels of calcium and phosphate. The mechanism of action involves the direct inhibition of osteoclast activity, which decreases bone resorption. This results in less demineralization of the bone and therefore a decrease in the release of calcium and phosphate from the bone into the blood. Calcitonin has no direct effect on bone formation by osteoblasts. 

In summary, IL-1 and TNF-a activate mature osteoclasts indirectly via a primary effect on osteoblasts and by inhibiting osteoclast apoptosis. In addition, they increase osteoclast formation either by directly stimulating the proliferation of osteoclast precursors or by increasing the pro-osteoclastogenic capacity of bone stromal cells. Although in vitro TNF-a and IL-1 can apparently induce the development of TRAP+ osteoclasts in the absence of RANKL/RANK, all data seem to indicate that TNF-a and IL-1 potentiate osteoclast development via the activation of common second messenger systems, such as NF-/cB activation, and that the effects on OCS require the RANKL/RANK system (Jones et al. 2002). 

Devlin RD, Reddy SV, Savino R, Ciliberto G, Roodman GD (1998) IL-6 mediates the effects of IL-1 or TNF, but not PTHrP or l,25(OH)2D3, on osteoclast-like cell formation in normal human bone marrow cultures. J Bone Miner Res 13 393-399... 

The most extensively used animal model to evaluate the action of SERMs on bone has been the ovariectomized (OVX) rat. In rats, tamoxifen antagonizes bone resorption and uterine growth (Turner et al. 1987,1988) and reduces the number and size of osteoclasts. The inhibitory effect on bone resorption of tamoxifen has also been reported in dogs and immobilized male rats (Wakley et al. 1988 Waters et al. 1991). As an antiresorptive agent, however, tamoxifen is less effective than 17/3-estradiol (17/9E2) (Williams et al. 1991) and has no effect when the endogenous production of estrogens is normal (Evans et al. 1994). 

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. 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

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