title: IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis.
abstract: Interleukin-17A (IL-17A) plays a pathogenic role in several rheumatic diseases including spondyloarthritis and, paradoxically, has been described to both promote and protect from bone formation. We therefore examined the effects of IL-17A on osteoblast differentiation in vitro and on periosteal bone formation in an in vivo model of inflammatory arthritis.
  
  
  
  K/BxN serum transfer arthritis was induced in IL-17A-deficient and wild-type mice. Clinical and histologic inflammation was assessed and periosteal bone formation was quantitated. Murine calvarial osteoblasts were differentiated in the continuous presence of IL-17A with or without blockade of secreted frizzled related protein (sFRP)1 and effects on differentiation were determined by qRT-PCR and mineralization assays. The impact of IL-17A on expression of Wnt signaling pathway antagonists was also assessed by qRT-PCR. Finally, regulation of Dickkopf (DKK)1 expression in murine synovial fibroblasts was evaluated after treatment with IL-17A, TNF, or IL-17A plus TNF.
  
  
  
  IL-17A-deficient mice develop significantly more periosteal bone than wild-type mice at peak inflammation, despite comparable severity of inflammation and bone erosion. IL-17A inhibits calvarial osteoblast differentiation in vitro, inducing mRNA expression of the Wnt antagonist sFRP1 in osteoblasts, and suppressing sFRP3 expression, both potentially contributing to inhibition of osteoblast differentiation. Furthermore, a blocking antibody to sFRP1 reduced the inhibitory effect of IL-17A on differentiation. Although treatment with IL-17A suppresses DKK1 mRNA expression in osteoblasts, IL-17A plus TNF synergistically upregulate DKK1 mRNA expression in synovial fibroblasts.
  
  
  
  IL-17A may limit the extent of bone formation at inflamed periosteal sites in spondyloarthritis. IL-17A inhibits calvarial osteoblast differentiation, in part by regulating expression of Wnt signaling pathway components. These results demonstrate that additional studies focusing on the role of IL-17A in bone formation in spondyloarthritis are indicated.
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, 364 Plantation Street, Suite 223, Worcester, MA, 01605, USA.
authors.forename: Anita T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, 364 Plantation Street, Suite 223, Worcester, MA, 01605, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, 364 Plantation Street, Suite 223, Worcester, MA, 01605, USA. ellen.gravallese@umassmed.edu.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D020381:Interleukin-17 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D010521:Periosteum / Q000473:pathology*; D016133:Polymerase Chain Reaction; D025241:Spondylarthritis / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17
keywords: Bone; Interleukin-17; Osteoblasts; Spondyloarthritis; Wnt signaling