{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:24:26Z","timestamp":1790630666704,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2012,7,13]],"date-time":"2012-07-13T00:00:00Z","timestamp":1342137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Bone homeostasis requires stringent regulation of osteoclasts, which secrete proteolytic enzymes to degrade the bone matrix. Despite recent progress in understanding how bone resorption occurs, the mechanisms regulating osteoclast secretion, and in particular the trafficking route of cathepsin K vesicles, remain elusive. Using a genetic approach, we describe the requirement for protein kinase C\u2013delta (PKC\u03b4) in regulating bone resorption by affecting cathepsin K exocytosis. Importantly, PKC\u03b4 deficiency does not perturb formation of the ruffled border or trafficking of lysosomal vesicles containing the vacuolar-ATPase (v-ATPase). Mechanistically, we find that cathepsin K exocytosis is controlled by PKC\u03b4 through modulation of the actin bundling protein myristoylated alanine-rich C-kinase substrate (MARCKS). The relevance of our finding is emphasized in vivo because PKC\u03b4\u2212\/\u2212 mice exhibit increased bone mass and are protected from pathological bone loss in a model of experimental postmenopausal osteoporosis. Collectively, our data provide novel mechanistic insights into the pathways that selectively promote secretion of cathepsin K lysosomes independently of ruffled border formation, providing evidence of the presence of multiple mechanisms that regulate lysosomal exocytosis in osteoclasts. \u00a9 2012 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1701","type":"journal-article","created":{"date-parts":[[2012,7,14]],"date-time":"2012-07-14T03:06:09Z","timestamp":1342235169000},"page":"2452-2463","source":"Crossref","is-referenced-by-count":54,"title":["Protein kinase C\u2013delta deficiency perturbs bone homeostasis by selective uncoupling of cathepsin K secretion and ruffled border formation in osteoclasts"],"prefix":"10.1093","volume":"27","author":[{"given":"Viviana","family":"Cremasco","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne E","family":"Decker","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Stumpo","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, National Institute of Environmental Health Science, Research Triangle Park, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perry J","family":"Blackshear","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction, National Institute of Environmental Health Science, Research Triangle Park, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi I","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traian S","family":"Lupu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah V","family":"Novack","sequence":"additional","affiliation":[{"name":"Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA"},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Faccio","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Washington University School of Medicine, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,7,13]]},"reference":[{"issue":"2","key":"2024020318320421100_bib1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nrm732","article-title":"Secretory lysosomes","volume":"3","author":"Blott","year":"2002","journal-title":"Nat Rev Mol Cell Biol."},{"key":"2024020318320421100_bib2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev.pathmechdis.3.121806.151431","article-title":"The osteoclast: friend or foe?","volume":"3","author":"Novack","year":"2008","journal-title":"Annu Rev Pathol."},{"issue":"7","key":"2024020318320421100_bib3","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/nm1593","article-title":"Skeletal remodeling in health and disease","volume":"13","author":"Zaidi","year":"2007","journal-title":"Nat Med."},{"key":"2024020318320421100_bib4","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nrg1122","article-title":"Genetic regulation of osteoclast development and function","volume":"4","author":"Teitelbaum","year":"2003","journal-title":"Nat Rev Genet."},{"issue":"Pt 9","key":"2024020318320421100_bib5","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1242\/jcs.02838","article-title":"Spatiotemporal dynamics of actin-rich adhesion microdomains: influence of substrate flexibility","volume":"119","author":"Collin","year":"2006","journal-title":"J Cell Sci."},{"issue":"11","key":"2024020318320421100_bib6","first-page":"1031","article-title":"Immunolocalization of beta 3 subunit of integrins in osteoclast membrane","volume":"65","author":"Teti","year":"1989","journal-title":"Boll Soc Ital Biol Sper."},{"key":"2024020318320421100_bib7","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1242\/jcs.108.8.2729","article-title":"The osteoclast clear zone is a specialized cell-extracellular matrix adhesion structure","volume":"108","author":"Vaananen","year":"1995","journal-title":"J Cell Sci."},{"key":"2024020318320421100_bib8","doi-asserted-by":"crossref","first-page":"3985","DOI":"10.1242\/jcs.112.22.3985","article-title":"Role of avb3 integrin in osteoclast migration and formation of the sealing zone","volume":"112","author":"Nakamura","year":"1999","journal-title":"J Cell Sci."},{"key":"2024020318320421100_bib9","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1083\/jcb.106.6.1863","article-title":"Polarized secretion of lysosomal enzymes: co-distribution of cation-independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway","volume":"106","author":"Baron","year":"1988","journal-title":"J Cell Biol."},{"issue":"Pt 15","key":"2024020318320421100_bib10","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1242\/jcs.110.15.1767","article-title":"Endocytic pathway from the basal plasma membrane to the ruffled border membrane in bone-resorbing osteoclasts","volume":"110","author":"Palokangas","year":"1997","journal-title":"J Cell Sci."},{"issue":"3","key":"2024020318320421100_bib11","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1083\/jcb.111.3.1305","article-title":"Evidence for the presence of a proton pump of the vacuolar H(+)-ATPase type in the ruffled borders of osteoclasts","volume":"111","author":"Vaananen","year":"1990","journal-title":"J Cell Biol."},{"issue":"6","key":"2024020318320421100_bib12","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1083\/jcb.101.6.2210","article-title":"Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border","volume":"101","author":"Baron","year":"1985","journal-title":"J Cell Biol."},{"issue":"10","key":"2024020318320421100_bib13","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1359\/jbmr.1999.14.10.1654","article-title":"Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization","volume":"14","author":"Gowen","year":"1999","journal-title":"J Bone Miner Res."},{"key":"2024020318320421100_bib14","doi-asserted-by":"crossref","first-page":"12511","DOI":"10.1074\/jbc.271.21.12511","article-title":"Cathepsin K, but not Cathepsins B, L, or S, is abundantly expressed in human osteoclasts","volume":"271","author":"Drake","year":"1996","journal-title":"J Biol Chem."},{"issue":"11","key":"2024020318320421100_bib15","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1101\/gr.6.11.1050","article-title":"A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis","volume":"6","author":"Johnson","year":"1996","journal-title":"Genome Res."},{"key":"2024020318320421100_bib16","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1126\/science.273.5279.1236","article-title":"Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency","volume":"273","author":"Gelb","year":"1996","journal-title":"Science."},{"issue":"4","key":"2024020318320421100_bib17","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S1084952102000587","article-title":"Formation and function of the ruffled border in osteoclasts","volume":"13","author":"Stenbeck","year":"2002","journal-title":"Semin Cell Dev Biol."},{"key":"2024020318320421100_bib18","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/S0006-291X(02)00326-1","article-title":"Intracellular membrane trafficking pathways in bone-resorbing osteoclasts revealed by cloning and subcellular localization studies of small GTP-binding rab proteins","volume":"293","author":"Zhao","year":"2002","journal-title":"Biochem Biophys Res Commun."},{"issue":"42","key":"2024020318320421100_bib19","doi-asserted-by":"crossref","first-page":"39295","DOI":"10.1074\/jbc.M010999200","article-title":"Downregulation of small GTPase Rab7 impairs osteoclast polarization and bone resorption","volume":"276","author":"Zhao","year":"2001","journal-title":"J Biol Chem."},{"issue":"6","key":"2024020318320421100_bib20","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.devcel.2008.03.022","article-title":"Synaptotagmin VII regulates bone remodeling by modulating osteoclast and osteoblast secretion","volume":"14","author":"Zhao","year":"2008","journal-title":"Dev Cell."},{"issue":"8","key":"2024020318320421100_bib21","doi-asserted-by":"crossref","first-page":"e12208","DOI":"10.1371\/journal.pone.0012208","article-title":"Spatial regulation of membrane fusion controlled by modification of phosphoinositides","volume":"5","author":"Dumas","year":"2010","journal-title":"PLoS One."},{"issue":"11","key":"2024020318320421100_bib22","doi-asserted-by":"crossref","first-page":"3610","DOI":"10.1128\/MCB.00259-08","article-title":"Phospholipase Cgamma2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase","volume":"28","author":"Epple","year":"2008","journal-title":"Mol Cell Biol."},{"issue":"4","key":"2024020318320421100_bib23","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1073\/pnas.92.4.944","article-title":"MARCKS deficiency in mice leads to abnormal brain development and perinatal death","volume":"92","author":"Stumpo","year":"1995","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"6883","key":"2024020318320421100_bib24","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/416865a","article-title":"Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta","volume":"416","author":"Miyamoto","year":"2002","journal-title":"Nature."},{"issue":"6","key":"2024020318320421100_bib25","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1172\/JCI39650","article-title":"Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL\/M-CSF signaling and osteoclast polarization","volume":"120","author":"Ito","year":"2010","journal-title":"J Clin Invest."},{"issue":"3","key":"2024020318320421100_bib26","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1083\/jcb.200212082","article-title":"Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin","volume":"162","author":"Faccio","year":"2003","journal-title":"J Cell Biol."},{"issue":"2","key":"2024020318320421100_bib27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1034\/j.1600-0854.2003.40206.x","article-title":"Osteoclast ruffled border has distinct subdomains for secretion and degraded matrix uptake","volume":"4","author":"Mulari","year":"2003","journal-title":"Traffic."},{"issue":"3","key":"2024020318320421100_bib28","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/S0021-9258(18)53878-3","article-title":"The MARCKS family of cellular protein kinase C substrates","volume":"268","author":"Blackshear","year":"1993","journal-title":"J Biol Chem."},{"issue":"2","key":"2024020318320421100_bib29","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/0014-5793(87)81513-2","article-title":"Inhibition of actin polymerization by latrunculin A","volume":"213","author":"Coue","year":"1987","journal-title":"FEBS Lett."},{"issue":"6370","key":"2024020318320421100_bib30","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/356618a0","article-title":"MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin","volume":"356","author":"Hartwig","year":"1992","journal-title":"Nature."},{"issue":"7","key":"2024020318320421100_bib31","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1111\/j.1600-0854.2011.01203.x","article-title":"Disruption of the Man-6-P targeting pathway in mice impairs osteoclast secretory lysosome biogenesis","volume":"12","author":"van Meel","year":"2011","journal-title":"Traffic."},{"issue":"1","key":"2024020318320421100_bib32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.devcel.2006.11.003","article-title":"Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation","volume":"12","author":"Tu","year":"2007","journal-title":"Dev Cell."},{"issue":"2","key":"2024020318320421100_bib33","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s002239900095","article-title":"Effect of diacylglycerols on osteoclastic bone resorption","volume":"59","author":"Moonga","year":"1996","journal-title":"Calcif Tissue Int."},{"issue":"2","key":"2024020318320421100_bib34","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1748-1716.2007.01808.x","article-title":"Cytoskeletal control of vesicle transport and exocytosis in chromaffin cells","volume":"192","author":"Trifaro","year":"2008","journal-title":"Acta Physiol (Oxf)."},{"issue":"9","key":"2024020318320421100_bib35","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.2337\/db08-1371","article-title":"Insulin granule recruitment and exocytosis is dependent on p110gamma in insulinoma and human beta-cells","volume":"58","author":"Pigeau","year":"2009","journal-title":"Diabetes."},{"issue":"45","key":"2024020318320421100_bib36","doi-asserted-by":"crossref","first-page":"28214","DOI":"10.1016\/S0021-9258(18)46916-5","article-title":"Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles","volume":"269","author":"Kim","year":"1994","journal-title":"J Biol Chem."},{"issue":"14","key":"2024020318320421100_bib37","doi-asserted-by":"crossref","first-page":"9960","DOI":"10.1016\/S0021-9258(18)82158-5","article-title":"Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids","volume":"268","author":"Taniguchi","year":"1993","journal-title":"J Biol Chem."},{"issue":"6324","key":"2024020318320421100_bib38","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/351320a0","article-title":"Regulation by phosphorylation of reversible association of a myristoylated protein kinase C substrate with the plasma membrane","volume":"351","author":"Thelen","year":"1991","journal-title":"Nature."},{"issue":"Pt 1","key":"2024020318320421100_bib39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1113\/jphysiol.2004.064063","article-title":"Mitochondrial calcium sequestration and protein kinase C cooperate in the regulation of cortical F-actin disassembly and secretion in bovine chromaffin cells","volume":"560","author":"Cuchillo-Ibanez","year":"2004","journal-title":"J Physiol."},{"issue":"13","key":"2024020318320421100_bib40","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1091\/mbc.e09-03-0197","article-title":"Cortical F-actin, the exocytic mode, and neuropeptide release in mouse chromaffin cells is regulated by myristoylated alanine-rich C-kinase substrate and myosin II","volume":"20","author":"Doreian","year":"2009","journal-title":"Mol Biol Cell."},{"issue":"2","key":"2024020318320421100_bib41","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0896-6273(95)90291-0","article-title":"Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis","volume":"14","author":"Vitale","year":"1995","journal-title":"Neuron."},{"issue":"39","key":"2024020318320421100_bib42","doi-asserted-by":"crossref","first-page":"36757","DOI":"10.1074\/jbc.M006518200","article-title":"Chromaffin cell F-actin disassembly and potentiation of catecholamine release in response to protein kinase C activation by phorbol esters is mediated through myristoylated alanine-rich C kinase substrate phosphorylation","volume":"276","author":"Rose","year":"2001","journal-title":"J Biol Chem."},{"issue":"2","key":"2024020318320421100_bib43","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1152\/physrev.00031.2002","article-title":"Secretory granule exocytosis","volume":"83","author":"Burgoyne","year":"2003","journal-title":"Physiol Rev."},{"issue":"9","key":"2024020318320421100_bib44","doi-asserted-by":"crossref","first-page":"e1001152","DOI":"10.1371\/journal.pbio.1001152","article-title":"Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy","volume":"9","author":"Brown","year":"2011","journal-title":"PLoS Biol."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.1701","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/27\/12\/2452\/56560488\/1701_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/27\/12\/2452\/56560488\/1701_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:47:18Z","timestamp":1710341238000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/27\/12\/2452-2463\/7598293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,13]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2012,7,13]]},"published-print":{"date-parts":[[2012,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.1701","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,12,1]]},"published":{"date-parts":[[2012,7,13]]}}}