Proprotein convertase activation of aggrecanases in cartilage in situ
Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal fo...
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| Veröffentlicht in: | Archives of biochemistry and biophysics 2008-10, Vol.478 (1), p.43-51 |
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| container_title | Archives of biochemistry and biophysics |
| container_volume | 478 |
| creator | Malfait, Anne-Marie Arner, Elizabeth C. Song, Ruo-Hua Alston, James T. Markosyan, Stella Staten, Nicholas Yang, Zhiyong Griggs, David W. Tortorella, Micky D. |
| description | Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage
in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics. |
| doi_str_mv | 10.1016/j.abb.2008.07.012 |
| format | Article |
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in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.</description><identifier>ISSN: 0003-9861</identifier><identifier>EISSN: 1096-0384</identifier><identifier>DOI: 10.1016/j.abb.2008.07.012</identifier><identifier>PMID: 18671934</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ADAM Proteins - metabolism ; ADAMTS ; ADAMTS4 Protein ; ADAMTS5 Protein ; Aged ; Aged, 80 and over ; Aggrecanase ; Cartilage ; Cartilage - enzymology ; Cartilage - metabolism ; Endopeptidases - chemistry ; Enzyme Activation ; Humans ; Kinetics ; Metalloproteases ; Middle Aged ; Models, Biological ; Osteoarthritis ; Osteoarthritis - metabolism ; PACE4 ; Post-translational activation ; Procollagen N-Endopeptidase - metabolism ; Proprotein convertase ; Proprotein Convertases - metabolism ; Protein Processing, Post-Translational ; Serine Endopeptidases - metabolism</subject><ispartof>Archives of biochemistry and biophysics, 2008-10, Vol.478 (1), p.43-51</ispartof><rights>2008 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-c111441ea6b47cfdcdd1ab159bfe2a5e5d9616bbc47262ed127777ad985644023</citedby><cites>FETCH-LOGICAL-c417t-c111441ea6b47cfdcdd1ab159bfe2a5e5d9616bbc47262ed127777ad985644023</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0003986108003305$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18671934$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malfait, Anne-Marie</creatorcontrib><creatorcontrib>Arner, Elizabeth C.</creatorcontrib><creatorcontrib>Song, Ruo-Hua</creatorcontrib><creatorcontrib>Alston, James T.</creatorcontrib><creatorcontrib>Markosyan, Stella</creatorcontrib><creatorcontrib>Staten, Nicholas</creatorcontrib><creatorcontrib>Yang, Zhiyong</creatorcontrib><creatorcontrib>Griggs, David W.</creatorcontrib><creatorcontrib>Tortorella, Micky D.</creatorcontrib><title>Proprotein convertase activation of aggrecanases in cartilage in situ</title><title>Archives of biochemistry and biophysics</title><addtitle>Arch Biochem Biophys</addtitle><description>Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage
in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.</description><subject>ADAM Proteins - metabolism</subject><subject>ADAMTS</subject><subject>ADAMTS4 Protein</subject><subject>ADAMTS5 Protein</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aggrecanase</subject><subject>Cartilage</subject><subject>Cartilage - enzymology</subject><subject>Cartilage - metabolism</subject><subject>Endopeptidases - chemistry</subject><subject>Enzyme Activation</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Metalloproteases</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Osteoarthritis</subject><subject>Osteoarthritis - metabolism</subject><subject>PACE4</subject><subject>Post-translational activation</subject><subject>Procollagen N-Endopeptidase - metabolism</subject><subject>Proprotein convertase</subject><subject>Proprotein Convertases - metabolism</subject><subject>Protein Processing, Post-Translational</subject><subject>Serine Endopeptidases - metabolism</subject><issn>0003-9861</issn><issn>1096-0384</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9LxDAQxYMo7rr6AbxIT95aM2matniSZf0DC3rQc0iT6ZKl265JuuC3N2UXvDmXYZg3jzc_Qm6BZkBBPGwz1TQZo7TKaJlRYGdkDrQWKc0rfk7mlNI8rSsBM3Ll_ZZSAC7YJZlBJUqocz4nqw837N0Q0PaJHvoDuqA8JkoHe1DBDn0ytInabBxq1ceNTyahcsF2aoPT4G0Yr8lFqzqPN6e-IF_Pq8_la7p-f3lbPq1TzaEMqYYYgAMq0fBSt0YbA6qBom5aZKrAwtQCRNNoXjLB0AArYylTV4XgnLJ8Qe6PvjHy94g-yJ31GrtO9TiMXoq64CDiZwsCR6F2g_cOW7l3dqfcjwQqJ3ZyKyM7ObGTtJSRXby5O5mPzQ7N38UJVhQ8HgUYXzxYdNJri71GYyOeIM1g_7H_BQmjf1E</recordid><startdate>20081001</startdate><enddate>20081001</enddate><creator>Malfait, Anne-Marie</creator><creator>Arner, Elizabeth C.</creator><creator>Song, Ruo-Hua</creator><creator>Alston, James T.</creator><creator>Markosyan, Stella</creator><creator>Staten, Nicholas</creator><creator>Yang, Zhiyong</creator><creator>Griggs, David W.</creator><creator>Tortorella, Micky D.</creator><general>Elsevier Inc</general><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></search><sort><creationdate>20081001</creationdate><title>Proprotein convertase activation of aggrecanases in cartilage in situ</title><author>Malfait, Anne-Marie ; Arner, Elizabeth C. ; Song, Ruo-Hua ; Alston, James T. ; Markosyan, Stella ; Staten, Nicholas ; Yang, Zhiyong ; Griggs, David W. ; Tortorella, Micky D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-c111441ea6b47cfdcdd1ab159bfe2a5e5d9616bbc47262ed127777ad985644023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>ADAM Proteins - metabolism</topic><topic>ADAMTS</topic><topic>ADAMTS4 Protein</topic><topic>ADAMTS5 Protein</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Aggrecanase</topic><topic>Cartilage</topic><topic>Cartilage - enzymology</topic><topic>Cartilage - metabolism</topic><topic>Endopeptidases - chemistry</topic><topic>Enzyme Activation</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Metalloproteases</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Osteoarthritis</topic><topic>Osteoarthritis - metabolism</topic><topic>PACE4</topic><topic>Post-translational activation</topic><topic>Procollagen N-Endopeptidase - metabolism</topic><topic>Proprotein convertase</topic><topic>Proprotein Convertases - metabolism</topic><topic>Protein Processing, Post-Translational</topic><topic>Serine Endopeptidases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malfait, Anne-Marie</creatorcontrib><creatorcontrib>Arner, Elizabeth C.</creatorcontrib><creatorcontrib>Song, Ruo-Hua</creatorcontrib><creatorcontrib>Alston, James T.</creatorcontrib><creatorcontrib>Markosyan, Stella</creatorcontrib><creatorcontrib>Staten, Nicholas</creatorcontrib><creatorcontrib>Yang, Zhiyong</creatorcontrib><creatorcontrib>Griggs, David W.</creatorcontrib><creatorcontrib>Tortorella, Micky D.</creatorcontrib><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><jtitle>Archives of biochemistry and biophysics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Malfait, Anne-Marie</au><au>Arner, Elizabeth C.</au><au>Song, Ruo-Hua</au><au>Alston, James T.</au><au>Markosyan, Stella</au><au>Staten, Nicholas</au><au>Yang, Zhiyong</au><au>Griggs, David W.</au><au>Tortorella, Micky D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proprotein convertase activation of aggrecanases in cartilage in situ</atitle><jtitle>Archives of biochemistry and biophysics</jtitle><addtitle>Arch Biochem Biophys</addtitle><date>2008-10-01</date><risdate>2008</risdate><volume>478</volume><issue>1</issue><spage>43</spage><epage>51</epage><pages>43-51</pages><issn>0003-9861</issn><eissn>1096-0384</eissn><abstract>Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in osteoarthritis (OA). ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a proprotein convertase, but the specific family member responsible for aggrecanase activation in cartilage
in situ has not been identified. Here we describe purification of a proprotein convertase activity from human OA cartilage. Through biochemical characterization and the use of siRNA, PACE4 was identified as a proprotein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 was observed in the extracellular milieu of cartilage, resulting in aggrecan degradation. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18671934</pmid><doi>10.1016/j.abb.2008.07.012</doi><tpages>9</tpages></addata></record> |
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| subjects | ADAM Proteins - metabolism ADAMTS ADAMTS4 Protein ADAMTS5 Protein Aged Aged, 80 and over Aggrecanase Cartilage Cartilage - enzymology Cartilage - metabolism Endopeptidases - chemistry Enzyme Activation Humans Kinetics Metalloproteases Middle Aged Models, Biological Osteoarthritis Osteoarthritis - metabolism PACE4 Post-translational activation Procollagen N-Endopeptidase - metabolism Proprotein convertase Proprotein Convertases - metabolism Protein Processing, Post-Translational Serine Endopeptidases - metabolism |
| title | Proprotein convertase activation of aggrecanases in cartilage in situ |
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