Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, A disintegrin and metalloprotease 17 (ADAM17), ectodomain shedding, Frizzled-related protein gene (FRZB), interleukin-6 receptor (IL-6R), metalloprotease, osteoarthritis, secreted Frizzled-related proteins (sFRPs), SNPs (single nucleotide polymorphisms), NECROSIS-FACTOR-ALPHA, CONVERTING-ENZYME, HIP OSTEOARTHRITIS, SOLUBLE INTERLEUKIN-6, SPEMANN ORGANIZER, WNT ANTAGONIST, CANCER CELLS, FRZB, DOMAIN, INHIBITION, ADAM Proteins, ADAM17 Protein, Amino Acid Substitution, Cell Line, Tumor, Cell Membrane, Chondrocytes, Down-Regulation, Genetic Predisposition to Disease, HEK293 Cells, Humans, Mutagenesis, Site-Directed, Mutant Proteins, Osteoarthritis, Hip, Peptide Fragments, Protein Interaction Domains and Motifs, Proteins, Receptors, Interleukin-6, Recombinant Proteins, Up-Regulation, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, 3101 Biochemistry and cell biology

Abstract:

To avoid malformation and disease, tissue development and homeostasis are coordinated 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. This 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 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.