title: Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction.
abstract: Sclerostin, an inhibitor of the Wnt/β-catenin pathway, has anti-anabolic effects on bone formation by negatively regulating osteoblast differentiation. Mutations in the human sclerostin gene (SOST) lead to sclerosteosis with progressive skeletal overgrowth, whereas sclerostin-deficient (Sost(-/-)) mice exhibit increased bone mass and strength. Therefore, antibody-mediated inhibition of sclerostin is currently being clinically evaluated for the treatment of postmenopausal osteoporosis in humans. We report that in chronic TNFα (tumor necrosis factor α)-dependent arthritis, fibroblast-like synoviocytes constitute a major source of sclerostin and that either the lack of sclerostin or its antibody-mediated inhibition leads to an acceleration of rheumatoid arthritis (RA)-like disease in human TNFα transgenic (hTNFtg) mice with enhanced pannus formation and joint destruction. Inhibition of sclerostin also failed to improve clinical signs and joint destruction in the partially TNFα-dependent glucose-6-phosphate isomerase-induced arthritis mouse model, but ameliorated disease severity in K/BxN serum transfer-induced arthritis mouse model, which is independent of TNF receptor signaling, thus suggesting a specific role for sclerostin in TNFα signaling. Sclerostin effectively blocked TNFα- but not interleukin-1-induced activation of p38, a key step in arthritis development, pointing to a previously unrealized protective role of sclerostin in TNF-mediated chronic inflammation. The possibility of anti-sclerostin antibody treatment worsening clinical RA outcome under chronic TNFα-dependent inflammatory conditions in mice means that caution should be taken both when considering such treatment for inflammatory bone loss in RA and when using anti-sclerostin antibodies in patients with TNFα-dependent comorbidities.
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Wehmeyer
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Frank
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Beckmann
authors.affiliation: Institute of Immunology, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Böttcher
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Cromme
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: König
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Fennen
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Annelena
authors.initials: A
authors.lastname: Held
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Paruzel
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stratis
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Korb-Pap
authors.affiliation: Institute of Immunology, University Hospital Jena, 07743 Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.affiliation: Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Kramer
authors.affiliation: Nijmegen Centre for Molecular Life Sciences, 86525 Nijmegen, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany. thomas.pap@uni-muenster.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, 48149 Muenster, Germany.
authors.forename: Berno
authors.initials: B
authors.lastname: Dankbar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005819:Genetic Markers; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; C422903:SOST protein, human; C486030:Sost protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; D005956:Glucose-6-Phosphate Isomerase