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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\n      \u003Ch2\u003ESummary\u003C\/h2\u003E\n      \u003Cp id=\u0022p-1\u0022\u003EThis overview presents progress in bone biology and highlighted potential new targets for therapeutic intervention. Included are the basic anatomy and physiology of bone; recent progress in the comprehension of the processes of bone formation and degradation; and the potential of novel therapeutic agents for bone disease in arthritis and osteoporosis.\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Earthritis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emetabolic bone disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n      \u003Cp id=\u0022p-2\u0022\u003EDallas C. Jones, PhD, Harvard Medical School, Boston, Massachusetts, USA, provided an overview of progress in bone biology and highlighted potential new targets for therapeutic intervention. His presentation included the basic anatomy and physiology of bone; recent progress in the comprehension of the processes of bone formation and degradation; and the potential of novel therapeutic agents for bone disease in arthritis and osteoporosis.\u003C\/p\u003E\n      \u003Cp id=\u0022p-3\u0022\u003EThe skeleton is an elaborate structure made of bones and cartilage, articulating with one another to serve important mechanical, metabolic, and microenvironmental functions. These include locomotion, the protection of vital organs, lodging of hematopoiesis, and mineral homeostasis [Teti A. \u003Cem\u003ECurr Osteoporos Rep\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-4\u0022\u003ERemodeling is a highly balanced process that involves the orchestration of bone cell activities (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). It involves the removal of old or damaged bone by osteoclasts (ie, bone-resorbing cells) and the subsequent replacement by new bone, formed by osteoblasts (ie, bone-forming cells; \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Feng X, McDonald JM. \u003Cem\u003EAnnu Rev Pathol Mech Dis\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\n         \u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\n            \n               \u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Bone Remodeling and Outcomes.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1218421574\u0022 data-figure-caption=\u0022Bone Remodeling and Outcomes.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\n            \n            \n         \u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12631\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\n         \u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\n            \u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003EBone Remodeling and Outcomes.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from Annual Reviews Inc. Copyright \u00a9 2010. All rights reserved.\u003C\/q\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\n      \u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\n         \u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\n            \n               \u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Osteoblast Basics.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1218421574\u0022 data-figure-caption=\u0022Osteoblast Basics.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\n            \n            \n         \u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/11\/13\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12632\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\n         \u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\n            \u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EOsteoblast Basics.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from Annual Reviews Inc. Copyright \u00a9 2010. All rights reserved.\u003C\/q\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\n      \u003Cp id=\u0022p-7\u0022\u003ETo prevent alterations in bone mass or quality after each remodeling cycle, bone resorption and formation must be tightly coupled. However, a variety of factors (eg, menopause-associated hormonal changes, drugs, age-related factors) can derail the process. Disequilibrium, in turn, leads to dysfunctions that can be seen in several bone diseases, including osteoporosis [Robling AG, Turner CH. \u003Cem\u003ECrit Rev Eukaryot Gene Expr\u003C\/em\u003E 2009; Feng X, McDonald JM. \u003Cem\u003EAnnu Rev Pathol\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-8\u0022\u003EOsteoporosis is a major public health issue that will only get worse as the population ages. In the United States, an estimated 55% of those aged \u226550 years are at risk for osteporotic fractures. In 2025, more than 3 million osteoporotic fractures are expected, with associated costs rising to approximately $25.3 billion [National Osteoporosis Foundation. \u003Ca href=\u0022http:\/\/www.nof.org\u0022\u003Ewww.nof.org\u003C\/a\u003E 2011].\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n      \u003Ch2 class=\u0022\u0022\u003EAnticatabolic Therapeutics\u003C\/h2\u003E\n      \u003Cp id=\u0022p-9\u0022\u003EAnticatabolic therapeutic interventions target resorptive and anabolic events. The former includes biphosphonates (BPs), cathepsin K inhibitors, and receptor activator of NF-\u03baB ligand (RANKL) inhibitors [Luhmann T et al. \u003Cem\u003EJ Control Release\u003C\/em\u003E 2011]; the latter includes Wnt\/LRP5, Eph\/Ephrins, Sema4D\/PlexinB1, and Schnurri-3. During his presentation, Dr. Jones discussed current and emerging therapeutics.\u003C\/p\u003E\n      \u003Cp id=\u0022p-10\u0022\u003EBPs reduce osteoclastic activity through inhibition of farnesyl diphosphate synthase, which leads to a loss in guanosine triphosphate (GTP)-binding proteins. These proteins are the key to osteoclastic activity, and it is the interference within the mevalonate pathway that stops osteoclastic activity and bone resorption [Russell RG et al. \u003Cem\u003EAnn NY Acad Sci\u003C\/em\u003E 2007].\u003C\/p\u003E\n      \u003Cp id=\u0022p-11\u0022\u003ERANKL, a member of the tumor necrosis factor family, is pivotal in osteoclastogenesis, as well as in mature osteoclast activity [Luhmann T et al. J \u003Cem\u003EControl Release\u003C\/em\u003E 2011]. Recent data suggest that osteocytes are the major source of RANKL in bone remodeling \u003Cem\u003Ein vivo\u003C\/em\u003E [Nakashima T et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2011]. Denosumab, a fully human monoclonal antibody, acts by binding to and inhibiting RANKL, leading to the loss of osteoclasts from bone surfaces [Baron R et al. \u003Cem\u003EBone\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-12\u0022\u003ECathepsin K, a lysomal cysteine protease that is involved in osteoclast-mediated bone resorption and inhibition, is a potentially attractive therapeutic approach for treating diseases that are characterized by excessive bone resorption [Wijkmans J, Gossen J. \u003Cem\u003EExpert Opin Ther Pat\u003C\/em\u003E 2011]. Most compounds are peptide-derived inhibitors that display a reversible binding nitrile or ketone warhead. Their clinical success will be determined by the selectivity that can be achieved against other off-target cathepsins. Current Phase 2 and Phase 3 clinical trials of ONO-5334 and odanacatib, respectively, may determine the future of these agents as disease-modifying therapeutics [Wijkmans J, Gossen \u003Cem\u003EJ. Expert Opin Ther Pat\u003C\/em\u003E 2011].\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n      \u003Ch2 class=\u0022\u0022\u003EAnabolic Therapeutics\u003C\/h2\u003E\n      \u003Cp id=\u0022p-13\u0022\u003EThe Lrp5 gene in the wnt pathway is a major determinant of bone mass accrual. Data indicate that circulating serotonin levels mediate the increased bone mass that result from gain-of-function mutations in Lrp5 in humans [Frost M. et al. \u003Cem\u003EJ Bone Miner Res\u003C\/em\u003E 2010]. Lrp5 signaling functions locally, suggesting that increasing Lrp5 signaling in mature bone cells may be a strategy for treating human disorders that are associated with low bone mass [Cui Y et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-14\u0022\u003ESclerostin is secreted by the osteocyte network and preosteoclasts and binds to the Lrp5\/6 receptors on osteoblasts to inhibit wnt signaling. Preclinical results suggest that sclerostin is a pivotal negative regulator of bone formation in the aging skeleton [Li X et al. \u003Cem\u003EJ Bone Miner\u003C\/em\u003E Res 2009]. Sclerostin antibodies (AMG 785) are currently in Phase 2 development and have been reported to be well tolerated in Phase 1 trials [Padhi D et al. \u003Cem\u003EJ Bone Miner\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-15\u0022\u003EOsteoclasts express the NFATc1 target gene Efnb2 (encoding ephrinB2), while osteoblasts express the receptor EphB4, along with other ephrin-Eph family members. Gain- and loss-of-function experiments demonstrate that reverse signaling through ephrinB2 in osteoclast precursors suppresses osteoclast differentiation by inhibiting the osteoclastogenic c-Fos-NFATc1 cascade.\u003C\/p\u003E\n      \u003Cp id=\u0022p-16\u0022\u003EIn addition, forward signaling through EphB4 to osteoblasts enhances osteogenic differentiation, and overexpression of EphB4 in osteoblasts increases bone mass in transgenic mice. These data demonstrate that ephrin-Eph bidirectional signaling links two major molecular mechanisms for cell differentiation\u2014one in osteoclasts and the other in osteoblasts\u2014thereby maintaining bone homeostasis [Zhao C et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2006].\u003C\/p\u003E\n      \u003Cp id=\u0022p-17\u0022\u003ESema4D, an axon guidance molecule that potentially inhibits bone formation, has emerged as a new therapeutic target for the discovery and development of bone-increasing drugs. Binding of Sema4D to its receptor, Plexin-B1, on osteoblasts results in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 signaling and by modulating osteoblast motility [Negishi-Koga T et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003Cp id=\u0022p-18\u0022\u003EInitial in vitro studies report various functions for mammalian Schnurri (Shn) proteins. Mice that bear parallel null mutations in the adapter proteins Shn2 and Shn3 exhibit defects in patterning of the axial skeleton during embryogenesis. Postnatally, these compound mutant mice develop unique osteochondrodysplasia.\u003C\/p\u003E\n      \u003Cp id=\u0022p-19\u0022\u003EThe deletion of Shn 2 and Shn3 impairs growth plate maturation during endochondrial ossification but simultaneously results in massively elevated trabecular bone formation. These findings indicate that growth plate maturation and bone formation can be uncoupled under certain circumstances and that unique and redundant functions that reside in the Schnurri protein family are required for proper skeletal patterning and remodeling [Jones DC et al. \u003Cem\u003EPNAS\u003C\/em\u003E 2010].\u003C\/p\u003E\n   \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/11\/13\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmw81\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmw81\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}