title: Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway.
abstract: OBJECTIVE
  Inflammation in the bone microenvironment stimulates osteoclast differentiation, resulting in uncoupling of resorption and formation. Mechanisms contributing to the inhibition of osteoblast function in inflammatory diseases, however, have not been elucidated. Rheumatoid arthritis (RA) is a prototype of an inflammatory arthritis that results in focal loss of articular bone. The paucity of bone repair in inflammatory diseases such as RA raises compelling questions regarding the impact of inflammation on bone formation. The aim of this study was to establish the mechanisms by which inflammation regulates osteoblast activity.
  
  
  METHODS
  We characterized an innovative variant of a murine model of arthritis in which inflammation is induced in C57BL/6J mice by transfer of arthritogenic K/BxN serum and allowed to resolve.
  
  
  RESULTS
  In the setting of resolving inflammation, bone resorption ceased and appositional osteoblast-mediated bone formation was induced, resulting in repair of eroded bone. Resolution of inflammation was accompanied by striking changes in the expression of regulators of the Wnt/β-catenin pathway, which is critical for osteoblast differentiation and function. Down-regulation of the Wnt antagonists secreted frizzled-related protein 1 (sFRP1) and sFRP2 during the resolution phase paralleled induction of the anabolic and pro-matrix mineralization factors Wnt10b and DKK2, demonstrating the role of inflammation in regulating Wnt signaling.
  
  
  CONCLUSIONS
  Repair of articular bone erosion occurs in the setting of resolving inflammation, accompanied by alterations in the Wnt signaling pathway. These data imply that in inflammatory diseases that result in persistent articular bone loss, strict control of inflammation may not be achieved and may be essential for the generation of an anabolic microenvironment that supports bone formation and repair.
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Matzelle
authors.forename: Maxime A
authors.initials: MA
authors.lastname: Gallant
authors.forename: Keith W
authors.initials: KW
authors.lastname: Condon
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Walsh
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Manning
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001861:Bone Regeneration / Q000502:physiology; D038702:Follistatin-Related Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase; D051153:Wnt Proteins / Q000096:biosynthesis*; D060449:Wnt Signaling Pathway
chemical_list: C405060:Dkk2 protein, mouse; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase