Bone resorbing osteoclasts

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. 

Nesbitt SA, Horton MA. 1997. Trafficking of matrix collagens through bone-resorbing osteoclasts. Science 27 266-9. 

Berger, C.E., Horrocks, B.R., and Datta, H.K. 1999. Direct non-genomic effect of steroid hormones on superoxide generation in the bone resorbing osteoclasts. Mol. Cell. Endocrinol. 149, 53-59. 

Contrary to the original assumption which linked the inhibition of bone resorption solely to physico-chemical adsorption of the BP onto the bone surface, there is new evidence indicating cellular mechanisms of BP action, although a prerequisite of the biological activity is still the adsorption. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclasts after being internalized by them. 

Actions. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone-resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate) inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts. They also bind strongly to hydroxyapatite crystals and, in high doses, can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive efficacy. There is wide variation between these compoimds in terms of their capacity to inhibit... 

In vitro studies have shown that TRAcP 5b isoform remains intracellularly in macrophages and dendritic cells which only secrete the TRAcP 5a isoform [25]. Therefore, for clinical determinations it is assumed that the tartrate-resistant acid phosphatase activity associated with bone resorbing osteoclasts derives only from the TRAcP 5 b isoform. 

CEM Berger, BR Horrocks, HK Datta. cAMP-dependent inhibition is dominant in regulating superoxide production in the bone-resorbing osteoclasts. J Endocrin 158 311-318, 1998. 

Pamidronate disodium is a bisphosphonate which binds irreversibly to hydroxyapatite in bone. It is a strong inhibitor of bone resorption, reducing osteoclast or osteoclast precursor activity. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts. 

Berger et al. have studied bone-resorbing osteoclasts. In their manuscript, they study the impact of calcium ions in the extracellular environment of osteoclasts. It is believed that high concentration of extracellular calcium ions inhibits the osteoclast resorptive activity. The SECM studies of calcium ions and superoxide anion generation by bone-resorbing osteoclasts were performed on the surface of a bovine cortical bone slice. The detection scheme relied on the use of Ca +- and 02 -selective electrodes. Interestingly, the SECM measurements outline the adaptive nature of osteoclasts to even high calcium concentration environments. 

Gao and Yamaguchi, 1999b Mouse bone marrow cells cultured for 7 d with bone resorbing factors (PTH, PGE2, EPS) +/- genistein osteoclast formation assessed by TRAP enzyme Genistein (10 Yi0 M) inhibited osteoclast formation. Mechanism may involve cAMP signalling. 

Figure 3 The effect of an Src (-/-) knockout in mice as shown by differences in function and appearance of wild-type and Src-minus osteoclasts. The Src-minus osteoclasts lack the ruffled borders of a normal, resorbing osteoclast, but are viable and can adhere to bone. (From Ref. 8.)...

Kameda T, Mano H, Yuasa T, Mori Y, Miyazawa K, Shiokawa M, Nakamaru Y, Hiroi E, Hiura K, Kameda A, Yang NN, Hakeda Y, Kumegawa M (1997) Estrogen inhibits bone resorption by directly inducing apoptosis of thebone-resorbing osteoclasts. J Exp Med 186 489-495... 

Kameda T, Mano H, Yamada Y, Takai H, Amizuka N, Kobori M, Izumi N, Kawashima H, Ozawa H, Ikeda K, Kameda A, Hakeda Y, Kumegawa M. 1998. Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem Biophys Res Commun245 419—22. 

Osteopetrosis is another rare disease in humans that has been analyzed by IR imaging. Patients with this disease have bones that are like rock, impeding their mobility and increasing their pain. In many patients, the cause of the disease is the inability of the bone resorbing cells, osteoclasts, to remodel the bone. For this reason there is a persistence of calcified cartilage. The IR data demonstrated increased mineral content and decreased crystal size, consistent with the properties seen in the bones of animal models of this disease.13... 

Both cortical and trabecular bone are continuously remodeled through the formation of a bone-modeling unit (BMU), or cutter-cone this process involves activation of osteoclasts, leading to resorption of bone by osteoclasts and formation of new bone by osteoblasts on the site of the old, resorbed bone (Fig. 7) (Martin and Burr, 1989). Under normal physiological conditions (i.e., in the absence of either growth or disease) the dynamics of bone remodeling maintain bone homeostasis throughout a person s lifetime. 

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