title: Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis.
abstract: Local bone erosion and systemic bone loss are hallmarks of rheumatoid arthritis and cause progressive disability. Tumor necrosis factor (TNF) is a key mediator of arthritis and acts catabolically on bone by stimulating bone resorption and inhibiting bone formation. We hypothesized that the concerted action of anti-TNF, which reduces inflammation and parathyroid hormone (PTH), which stimulates bone formation, or osteoprotegerin (OPG), which blocks bone resorption and could lead to repair of local bone erosions and reversal of systemic bone loss. To test this, human TNF-transgenic mice with established erosive arthritis and systemic bone loss were treated with PTH, OPG, and anti-TNF, alone or in combination. Local bone erosions almost fully regressed, on combined treatment with anti-TNF and PTH and/or OPG, suggesting repair of inflammatory skeletal lesions. In contrast, OPG and anti-TNF alone led to arrest of bone erosions but did not achieve repair. Treatment with PTH alone had no influence on the progression of bone erosions. Local bone erosions all showed signs of new bone formation such as the presence of osteoblasts, osteoid formation, and mineralization. Furthermore, systemic bone loss was completely reversed on combined treatment and this effect was mediated by osteoblast stimulation and osteoclast blockade. In summary, we conclude that local joint destruction and systemic inflammatory bone loss because of TNF can regress and that repair requires a combined approach by reducing inflammation, blocking bone resorption, or stimulating bone formation.
authors.affiliation: Department of Internal Medicine III, University of Vienna, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Birgit
authors.initials: B
authors.lastname: Görtz
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Nicholas
authors.initials: N
authors.lastname: Doerr
authors.forename: Paul
authors.initials: P
authors.lastname: Kostenuik
authors.forename: Helga
authors.initials: H
authors.lastname: Bergmeister
authors.forename: George
authors.initials: G
authors.lastname: Kollias
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects* / Q000473:pathology; D004359:Drug Therapy, Combination; D006023:Glycoproteins / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D053244:Osteoprotegerin; D010281:Parathyroid Hormone / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000494:pharmacology
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha