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

Guillaume Courbon,Thierry Thomas,Maude Gerbaix,Laurence Vico,Robin Caire,Mireille Thomas,Marie-Thérèse Linossier,Raphaëlle Lamarque,Norbert Laroche,Hubert Marotte

doi:10.1038/s41598-018-21886-w

Guillaume Courbon, Thierry Thomas + Show 8 more

Open Access

https://doi.org/10.1038/s41598-018-21886-w

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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.

Highlights

Rheumatoid arthritis (RA) physiopathology includes synovial inflammation with proinflammatory cytokine overexpression of such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-171
The bone microarchitecture alteration was related to a strong decrease in bone osteoblastic activity and increased bone destruction, mainly after arthritis onset
We explored mechanisms explaining this imbalance before arthritis onset

Summary

Introduction

Rheumatoid arthritis (RA) physiopathology includes synovial inflammation with proinflammatory cytokine overexpression of such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-171 These events induce joint swelling, the first clinical sign observed in arthritis and considered as the disease onset[2]. In the female Lewis rat adjuvant-induced arthritis (AIA) model, ankle bone porosity was increased with trabecular bone loss at the day of clinical arthritis onset, occurring mainly at the navicular bone site[12]. These early signs predicted later inflammation and bone loss outcome. To investigate the clear role of Wnt inhibitors in relation to bone alteration in the early phases of arthritis, we explored periarticular cortical and trabecular bone microarchitecture at 7 different time points, before arthritis onset, and correlated the bone alteration with gene expressions focusing on Wnt inhibitors in the rat AIA model

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