Early sclerostin expression explains bone formation inhibition before arthritis onset in the rat adjuvant-induced arthritis model

Sci Rep. 2018 Feb 22;8(1):3492. doi: 10.1038/s41598-018-21886-w.

Abstract

Periarticular bone loss in rheumatoid arthritis (RA) is considered to be mainly related to synovial inflammation. However, strong bone loss has also described at the time of arthritis onset. Recently, a paradoxical exacerbation of joint damage was described when blocking sclerostin in various arthritis models. Thus, we aimed to determine kinetics of bone loss and its mechanisms in the adjuvant induced arthritis (AIA) rat model of RA. AIA was induced (n = 35) or not (n = 35) at day 0. In addition to well-known arthritis at day 12, we showed with 3D-imaging and histomorphometry that bone microstructural alterations occurred early from day 8 post-induction, characterized by cortical porosity and trabecular bone loss. Active osteoclastic surfaces were increased from day 8 with RANKL upregulation. More surprisingly SOST and DKK1 were overexpressed from day 6 and followed by a dramatic decrease in bone formation from day 8. At the time of arthritis onset, SOST and DKK1 returned to control values, but frizzled related protein 1 (SFRP1), proinflammatory cytokines, and MMPs started to increase. Bone alterations before arthritis onset reinforce the hypothesis of an early bone involvement in arthritis. Kinetics of osteocyte markers expression should be considered to refine Wnt inhibitor treatment strategies.

MeSH terms

  • Animals
  • Arthritis, Experimental / genetics*
  • Arthritis, Experimental / physiopathology
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / physiopathology
  • Bone Morphogenetic Proteins / genetics*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Genetic Markers / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Membrane Proteins / genetics
  • Osteoclasts / metabolism
  • Osteocytes / metabolism
  • Osteogenesis / genetics*
  • RANK Ligand / genetics
  • Rats

Substances

  • Bone Morphogenetic Proteins
  • Dkk1 protein, rat
  • Genetic Markers
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RANK Ligand
  • Sfrp1 protein, rat
  • Sost protein, rat