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.
abstract: To avoid malformation and disease, tissue development and homoeostasis are co-ordinated precisely in time and space. Secreted Frizzled-related protein 3 (sFRP3), encoded by the Frizzled-related protein gene (FRZB), acts as an antagonist of Wnt signalling in bone development by delaying the maturation of proliferative chondrocytes into hypertrophic chondrocytes. 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 in 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 in 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.
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Mirja
authors.initials: M
authors.lastname: Oldefest
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Düsterhöft
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Desel
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Thysen
authors.affiliation: Institute of Zoology, Molecular Physiology, Christian-Albrechts-University, Am Botanischen Garten 3-9, 24118 Kiel, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Fink
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Lories
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Olshausenstr. 40, 24098 Kiel, Germany ilorenzen@biochem.uni-kiel.de.
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D019902:Chondrocytes / Q000378:metabolism*; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D015207:Osteoarthritis, Hip / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015854:Up-Regulation; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D050505:Mutant Proteins; D010446:Peptide Fragments; D011506:Proteins; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D000094742:Secreted Frizzled-Related Proteins; C508603:IL6R protein, human; C000606462:ADAM17 protein, human
keywords: A disintegrin and metalloprotease 17 (ADAM17); Frizzled-related protein gene (FRZB); SNPs (single nucleotide polymorphisms); ectodomain shedding; interleukin-6 receptor (IL-6R); metalloprotease; osteoarthritis; secreted Frizzled-related proteins (sFRPs)