title: R-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the Wnt pathway.
abstract: OBJECTIVE
  During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis.
  
  
  METHODS
  Tumor necrosis factor alpha (TNFalpha)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts.
  
  
  RESULTS
  The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFalpha-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis.
  
  
  CONCLUSIONS
  Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture.
authors.affiliation: University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Michael
authors.initials: M
authors.lastname: Stock
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.forename: Cordula
authors.initials: C
authors.lastname: Surmann-Schmitt
authors.forename: Julia
authors.initials: J
authors.lastname: Luther
authors.forename: Julia
authors.initials: J
authors.lastname: Katzenbeisser
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: David
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Karolyn
authors.initials: K
authors.lastname: Tran
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Bright
authors.forename: Minke E
authors.initials: ME
authors.lastname: Binnerts
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Christina
authors.initials: C
authors.lastname: Böhm
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Distler
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Arie
authors.initials: A
authors.lastname: Abo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D017403:In Situ Hybridization; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019699:Thrombospondins / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: C518903:RSPO1 protein, mouse; D019699:Thrombospondins; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins