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Vikte Lionikaite, Karin L Gustafsson, Anna Westerlund, Sara H Windahl, Antti Koskela, Juha Tuukkanen, Helena Johansson, Claes Ohlsson, H Herschel Conaway, Petra Henning and Ulf H Lerner

associated with decreased bone strength ( Johansson et al. 2002 , Lind et al. 2011 ). This reduction in the amount of cortical bone has been attributed to an increase in the number of periosteal osteoclasts ( Trechsel et al. 1987 , Hough et al. 1988

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Wang Xiao, Fei Beibei, Shen Guangsi, Jiang Yu, Zhang Wen, Huang Xi and Xu Youjia

osteoclast generation, function, and survival ( Khosla et al . 2012 ). Estrogen has been shown to increase markers of oxidative stress in bone ( Khosla et al . 2012 ). We propose the hypothesis that estrogen deficiency and increased iron levels are the main

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S B Rodan and G A Rodan

Integrins are a large family of heteromeric cell surface receptors composed of non-covalently bound α and β subunits which interact with extracellular matrix molecules, serum constituents and the adhesion molecules of the immunoglobulin family. The extracellular domains of many integrins recognize the RGD (Arg-Gly-Asp) tripeptide found in several extracellular macromolecules such as fibronectin, vitronectin, fibrinogen and osteopontin. The vitronectin receptor, αvβ3 integrin, is highly expressed in osteoclasts, the bone resorbing cells, and binds many of these RGD containing proteins including osteopontin, which is abundant in bone. Antibodies to αvβ3, RGD peptides and RGD containing proteins such as echistatin, and kistrin were shown to inhibit bone resorption in vitro and in vivo. The identity of the αvβ3 natural ligand and its mode of action in bone are so far not known. In addition to the very high levels of αvβ3, mammalian osteoclasts also express α2β1, a collagen/laminin receptor and αvβ1, another vitronectin receptor. Signaling events that follow substrate recognition by osteoclasts are not well understood. RGD containing peptides and proteins modulate [Ca2+] transients in osteoclasts and phosphatidylinositol 3-kinase and pp60c-src are associated with αvβ3 in these cells. αv and β3 genes were shown to be regulated by the calciotropic hormone 1,25(OH)2D3 and by a number of cytokines known to be modulators of bone metabolism. In summary, elucidation of the interactions of osteoclast integrins with components of bone matrix, may lead to further understanding of the mechanism of bone resorption.

Journal of Endocrinology (1997) 154, S47–S56

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Masaki Nakano, Mika Ikegame, Junko Igarashi-Migitaka, Yusuke Maruyama, Nobuo Suzuki and Atsuhiko Hattori

turnover ( Amstrup et al. 2013 ). Another amine hormone, calcitonin, an osteoclast-suppressing hormone, is primarily secreted by C cells of the thyroid gland in mammals or the ultimobranchial gland in lower vertebrates, including chickens. Bone tissue

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Charlotte E Combs, Karen Fuller, Hashethra Kumar, Anthony P Albert, Grisha Pirianov, James McCormick, Ian C Locke, Timothy J Chambers and Kevin M Lawrence

osteoclasts. Osteoclasts are derived from the monocyte macrophage lineage; they are large multinucleated cells and are the only cells of the body capable of resorbing bone. They mature to form large tartrate-resistant acid phosphatase (TRAP) positive

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David J Mellis, Cecile Itzstein, Miep H Helfrich and Julie C Crockett

Introduction Osteoclasts are required during skeletal development to form and shape bones and throughout life in the process of remodelling that maintains the bone tissue in a healthy state by the continual repair of microfractures (reviewed in

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Ke Ke, Ok-Joo Sul, Soo-Wol Chung, Jae-Hee Suh and Hye-Seon Choi

K, O J S and H S C. References Cappellen D Luong-Nguyen N Bongiovanni S Grenet O Wanke C Susa M 2002 Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony stimulating factor

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Susanne Granholm, Pernilla Lundberg and Ulf H Lerner

-cells ( Foster et al . 1964 , Zaidi et al . 2002 ). The hypocalcaemic response is mainly due to inhibition of bone resorption ( Friedman & Raisz 1965 ), caused by activation of CT receptors (CTRs) in mature osteoclasts leading to contraction, ceased motility

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CP Carron, DM Meyer, VW Engleman, JG Rico, PG Ruminski, RL Ornberg, WF Westlin and GA Nickols

Osteoclasts are actively motile on bone surfaces and undergo alternating cycles of migration and resorption. Osteoclast interaction with the extracellular matrix plays a key role in the osteoclast resorptive process and a substantial body of evidence suggests that integrin receptors are important in osteoclast function. These integrin receptors bind to the Arg-Gly-Asp (RGD) sequence found in a variety of extracellular matrix proteins and it is well established that the interaction of osteoclast alpha v beta 3 integrin with the RGD motif within bone matrix proteins is important in osteoclast-mediated bone resorption. In this study, we characterized the effects of two synthetic peptidomimetic antagonists of alpha v beta 3, SC-56631 and SC-65811, on rabbit osteoclast adhesion to purified matrix proteins and bone, and on bone resorption in vitro. SC-56631 and SC-65811 are potent inhibitors of vitronectin binding to purified alpha v beta 3. Both SC-56631 and SC-65811 inhibited osteoclast adhesion to osteopontin- and vitronectin-coated surfaces and time-lapse video microscopy showed that osteoclasts rapidly retract from osteopontin-coated surfaces when exposed to SC-56631 and SC-65811. SC-56631 and SC-65811 blocked osteoclast-mediated bone resorption in a dose-responsive manner. Further analysis showed that SC-65811 and SC-56631 reduced the number of resorption pits produced per osteoclast and the average pit size. SC-65811 was a more potent inhibitor of bone resorption and the combination of reduced pit number and size led to a 90% inhibition of bone resorption. Surprisingly, however, osteoclasts treated with SC-65811, SC-56631 or the disintegrin echistatin, at concentrations that inhibit bone resorption did not inhibit osteoclast adhesion to bone. These results suggest that alphavbeta3 antagonists inhibited bone resorption by decreasing osteoclast bone resorptive activity or efficiency but not by inhibiting osteoclast adhesion to bone per se.

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S Morishima, I Morita, T Tokushima, H Kawashima, M Miyasaka, K Omura and S Murota

Osteoclasts are formed from hematopoietic precursors via cell-cell fusion. We have previously reported that mannose residues are expressed on the outer membranes of monocytes during osteoclast differentiation. In the present study, we have attempted to demonstrate the pattern of expression levels of terminal high-mannose type oligosaccharide and to show that the mannose receptor is expressed on osteoclast precursor cells. Osteoclasts were formed using three different systems, namely mouse bone marrow cell culture, co-culture of mouse spleen cells with stromal cells, and RAW264.7 cell cultures. During osteoclast differentiation, the expression of terminal high-mannose type oligosaccharide gradually increased and then peaked at the stage of fusion in all three systems. Expression of the mannose receptor gradually increased during osteoclast differentiation in bone marrow cells and the co-culture system. In contrast, that in RAW264.7 cells had already been detected in the absence of the soluble receptor activator of NF-kappaB ligand and did not change during osteoclast differentiation. To ascertain whether expression of high-mannose type oligosaccharide is involved in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell (MNC) formation, glycosidase inhibitors were used on RAW264.7 cell culture. Castanospermine, an inhibitor of glucosidase I, inhibited the TRAP-positive MNCs, and deoxymannojirimycin, an inhibitor of alpha-mannosidase I, increased the TRAP-positive MNC formation. These results indicate that the binding of terminal high-mannose and mannose receptor is important for the process of cellular fusion in osteoclast formation.