Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone
Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cell...
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| Veröffentlicht in: | The American journal of pathology 2004-08, Vol.165 (2), p.593-600 |
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| creator | Lindeman, Jan H.N. Hanemaaijer, Roeland Mulder, Adri Dijkstra, P.D. Sander Szuhai, Károly Bromme, Dieter Verheijen, Jan H. Hogendoorn, Pancras C.W. |
| description | Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H
+-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT. |
| doi_str_mv | 10.1016/S0002-9440(10)63323-8 |
| format | Article |
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+-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/S0002-9440(10)63323-8</identifier><identifier>PMID: 15277232</identifier><identifier>CODEN: AJPAA4</identifier><language>eng</language><publisher>Bethesda, MD: Elsevier Inc</publisher><subject>Adult ; Biological and medical sciences ; Bone Neoplasms - enzymology ; Bone Neoplasms - pathology ; Cathepsin K ; Cathepsin L ; Cathepsins - metabolism ; Collagenases - metabolism ; Cysteine Endopeptidases - metabolism ; Female ; Giant Cell Tumor of Bone - enzymology ; Giant Cell Tumor of Bone - pathology ; Humans ; Immunoenzyme Techniques ; Investigative techniques, diagnostic techniques (general aspects) ; Male ; Matrix Metalloproteinase 13 ; Matrix Metalloproteinases, Membrane-Associated ; Medical sciences ; Metalloendopeptidases - metabolism ; Middle Aged ; Osteoclasts - metabolism ; Osteoclasts - pathology ; Osteolysis - enzymology ; Osteolysis - pathology ; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques ; Regular ; RNA, Messenger - metabolism</subject><ispartof>The American journal of pathology, 2004-08, Vol.165 (2), p.593-600</ispartof><rights>2004 American Society for Investigative Pathology</rights><rights>2004 INIST-CNRS</rights><rights>Copyright © American Society for Investigative Pathology 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c642t-516be1bd6989bd56f75012f189b5a92642edd09311877ce0531df9aeb749347e3</citedby><cites>FETCH-LOGICAL-c642t-516be1bd6989bd56f75012f189b5a92642edd09311877ce0531df9aeb749347e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618565/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002944010633238$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,3537,27901,27902,53766,53768,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15975271$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15277232$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lindeman, Jan H.N.</creatorcontrib><creatorcontrib>Hanemaaijer, Roeland</creatorcontrib><creatorcontrib>Mulder, Adri</creatorcontrib><creatorcontrib>Dijkstra, P.D. Sander</creatorcontrib><creatorcontrib>Szuhai, Károly</creatorcontrib><creatorcontrib>Bromme, Dieter</creatorcontrib><creatorcontrib>Verheijen, Jan H.</creatorcontrib><creatorcontrib>Hogendoorn, Pancras C.W.</creatorcontrib><title>Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H
+-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT.</description><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Bone Neoplasms - enzymology</subject><subject>Bone Neoplasms - pathology</subject><subject>Cathepsin K</subject><subject>Cathepsin L</subject><subject>Cathepsins - metabolism</subject><subject>Collagenases - metabolism</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Female</subject><subject>Giant Cell Tumor of Bone - enzymology</subject><subject>Giant Cell Tumor of Bone - pathology</subject><subject>Humans</subject><subject>Immunoenzyme Techniques</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Male</subject><subject>Matrix Metalloproteinase 13</subject><subject>Matrix Metalloproteinases, Membrane-Associated</subject><subject>Medical sciences</subject><subject>Metalloendopeptidases - metabolism</subject><subject>Middle Aged</subject><subject>Osteoclasts - metabolism</subject><subject>Osteoclasts - pathology</subject><subject>Osteolysis - enzymology</subject><subject>Osteolysis - pathology</subject><subject>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</subject><subject>Regular</subject><subject>RNA, Messenger - metabolism</subject><issn>0002-9440</issn><issn>1525-2191</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkEFvFCEUx4nR2LX6ETRcNHoY5cEAw0VTN1obm2hiPROGedOlmRlGmK3x28t2N209eYIHv_fn8SPkObC3wEC9-8EY45Wpa_Ya2BslBBdV84CsQHJZcTDwkKxukSPyJOerUirRsMfkqEBac8FX5GTtlg3OOUz0Kz3LtBT0ewqTD7Mbyi4u6DLScn0a3LTQNQ4DvdiOMdHY049xwqfkUe-GjM8O6zH5-fnTxfpLdf7t9Gx9cl55VfOlkqBahLZTpjFtJ1WvJQPeQ6mkM7ww2HXMCIBGa49MCuh647DVtRG1RnFM3u9z5207YudxWpIb7JzC6NIfG12w_95MYWMv47UFBY1UsgS8OgSk-GuLebFjyL78x00Yt9kqpWtVN00B5R70KeacsL99BJjdybc38u3O7O7oRr7d9b24P-Fd18F2AV4eAJe9G_rkiud8jzO6oHA36SZcbn6HhDaPbhhKLFh3NYOSlltpRAE_7EEs4q8DJpt9wMljV5r8YrsY_jPzX_g8rKI</recordid><startdate>20040801</startdate><enddate>20040801</enddate><creator>Lindeman, Jan H.N.</creator><creator>Hanemaaijer, Roeland</creator><creator>Mulder, Adri</creator><creator>Dijkstra, P.D. Sander</creator><creator>Szuhai, Károly</creator><creator>Bromme, Dieter</creator><creator>Verheijen, Jan H.</creator><creator>Hogendoorn, Pancras C.W.</creator><general>Elsevier Inc</general><general>ASIP</general><general>American Society for Investigative Pathology</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040801</creationdate><title>Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone</title><author>Lindeman, Jan H.N. ; Hanemaaijer, Roeland ; Mulder, Adri ; Dijkstra, P.D. Sander ; Szuhai, Károly ; Bromme, Dieter ; Verheijen, Jan H. ; Hogendoorn, Pancras C.W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c642t-516be1bd6989bd56f75012f189b5a92642edd09311877ce0531df9aeb749347e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Bone Neoplasms - enzymology</topic><topic>Bone Neoplasms - pathology</topic><topic>Cathepsin K</topic><topic>Cathepsin L</topic><topic>Cathepsins - metabolism</topic><topic>Collagenases - metabolism</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Female</topic><topic>Giant Cell Tumor of Bone - enzymology</topic><topic>Giant Cell Tumor of Bone - pathology</topic><topic>Humans</topic><topic>Immunoenzyme Techniques</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Male</topic><topic>Matrix Metalloproteinase 13</topic><topic>Matrix Metalloproteinases, Membrane-Associated</topic><topic>Medical sciences</topic><topic>Metalloendopeptidases - metabolism</topic><topic>Middle Aged</topic><topic>Osteoclasts - metabolism</topic><topic>Osteoclasts - pathology</topic><topic>Osteolysis - enzymology</topic><topic>Osteolysis - pathology</topic><topic>Pathology. 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Sander</creatorcontrib><creatorcontrib>Szuhai, Károly</creatorcontrib><creatorcontrib>Bromme, Dieter</creatorcontrib><creatorcontrib>Verheijen, Jan H.</creatorcontrib><creatorcontrib>Hogendoorn, Pancras C.W.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The American journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lindeman, Jan H.N.</au><au>Hanemaaijer, Roeland</au><au>Mulder, Adri</au><au>Dijkstra, P.D. Sander</au><au>Szuhai, Károly</au><au>Bromme, Dieter</au><au>Verheijen, Jan H.</au><au>Hogendoorn, Pancras C.W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone</atitle><jtitle>The American journal of pathology</jtitle><addtitle>Am J Pathol</addtitle><date>2004-08-01</date><risdate>2004</risdate><volume>165</volume><issue>2</issue><spage>593</spage><epage>600</epage><pages>593-600</pages><issn>0002-9440</issn><eissn>1525-2191</eissn><coden>AJPAA4</coden><abstract>Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H
+-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT.</abstract><cop>Bethesda, MD</cop><pub>Elsevier Inc</pub><pmid>15277232</pmid><doi>10.1016/S0002-9440(10)63323-8</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Biological and medical sciences Bone Neoplasms - enzymology Bone Neoplasms - pathology Cathepsin K Cathepsin L Cathepsins - metabolism Collagenases - metabolism Cysteine Endopeptidases - metabolism Female Giant Cell Tumor of Bone - enzymology Giant Cell Tumor of Bone - pathology Humans Immunoenzyme Techniques Investigative techniques, diagnostic techniques (general aspects) Male Matrix Metalloproteinase 13 Matrix Metalloproteinases, Membrane-Associated Medical sciences Metalloendopeptidases - metabolism Middle Aged Osteoclasts - metabolism Osteoclasts - pathology Osteolysis - enzymology Osteolysis - pathology Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Regular RNA, Messenger - metabolism |
| title | Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone |
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