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A disintegrin and metalloprotease 17 (ADAM17) is a transmembrane protease that is essential for developmental processes and promotes cartilage maturation into bone. sFRP3 is chondroprotective and is expressed in chondrocytes of healthy articular cartilage. Upon damage to cartilage, sFRP3 is down-regulated. Rare variants of sFRP3 are associated with osteoarthritis. The present study demonstrates a novel function of sFRP3\u00a0in suppression of the enzymatic activity of ADAM17 which results in the inhibition of ADAM17-meditated interleukin-6 receptor (IL-6R) shedding. By contrast, the rare double variant of sFRP3 failed to suppress ADAM17. The shed soluble IL-6R (sIL-6R) is linked to inflammation, cartilage degeneration and osteolysis. Accordingly, enhanced activity of ADAM17\u00a0in cartilage, caused by the expression of the rare double sFRP3 variant, provides an explanation for the genetic effect of sFRP3 variants in joint disease. The finding that sFRP3 interacts with the ADAM17 substrate IL-6R also suggests a new regulatory mechanism by which the substrate is protected against shedding.<\/jats:p>","DOI":"10.1042\/bj20141231","type":"journal-article","created":{"date-parts":[[2015,4,9]],"date-time":"2015-04-09T09:12:21Z","timestamp":1428570741000},"page":"507-518","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Secreted Frizzled-related protein 3 (sFRP3)-mediated suppression of interleukin-6 receptor release by A disintegrin and metalloprotease 17 (ADAM17) is abrogated in the osteoarthritis-associated rare double variant of sFRP3"],"prefix":"10.1042","volume":"468","author":[{"given":"Mirja","family":"Oldefest","sequence":"first","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"D\u00fcsterh\u00f6ft","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Desel","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Thysen","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Fink","sequence":"additional","affiliation":[{"name":"Institute of Zoology, Molecular Physiology, Christian-Albrechts-University, Am Botanischen Garten 3-9, 24118 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Rabe","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Lories","sequence":"additional","affiliation":[{"name":"Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Gr\u00f6tzinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inken","family":"Lorenzen","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2015,6,15]]},"reference":[{"key":"2021112216212281000_B1","doi-asserted-by":"publisher","first-page":"26131","DOI":"10.1074\/jbc.271.42.26131","article-title":"Primary structure and tissue distribution of FRZB, a novel protein related to Drosophila frizzled, suggest a role in skeletal morphogenesis","volume":"271","author":"Hoang","year":"1996","journal-title":"J. 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