R-spondins are newly recognized players in osteoarthritis that regulate Wnt signaling in osteoblasts
Article first published online: 29 NOV 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 12, pages 3865–3875, December 2011
How to Cite
Abed, É., Chan, T. F., Delalandre, A., Martel-Pelletier, J., Pelletier, J.-P. and Lajeunesse, D. (2011), R-spondins are newly recognized players in osteoarthritis that regulate Wnt signaling in osteoblasts. Arthritis & Rheumatism, 63: 3865–3875. doi: 10.1002/art.30625
- Issue published online: 29 NOV 2011
- Article first published online: 29 NOV 2011
- Accepted manuscript online: 30 AUG 2011 10:07AM EST
- Manuscript Accepted: 11 AUG 2011
- Manuscript Received: 18 OCT 2010
- Canadian Institutes of Health Research. Grant Number: MOP-49501
- Postdoctoral fellowship from the Osteoarthritis Chair of the University of Montreal
Clinical and in vitro studies suggest that altered osteogenesis or bone remodeling is involved in the progression and/or onset of osteoarthritis (OA). Wnt signaling plays a key role in osteogenesis via the canonical Wnt/β-catenin signaling pathway. Two of the R-spondins, Rspo-1 and Rspo-2, a family of 4 proteins unrelated to other Wnt ligands that act as Wnt agonists, are present in bone tissues. The purpose of this study was to investigate the potential role of Rspo-1 and Rspo-2 in OA osteoblasts.
Primary human normal and OA osteoblasts were prepared from tibial plateaus. The expression of Rspo-1 and Rspo-2 was evaluated by quantitative reverse transcription–polymerase chain reaction analysis. Western blot analysis was used to determine Rspo-2, β-catenin, and phospho–β-catenin levels. Wnt/β-catenin signaling was evaluated using the TOPflash T cell factor (TCF)/lymphoid enhancer factor (LEF) luciferase reporter assay. Mineralization was evaluated by alizarin red staining.
The expression of Rspo-1 was similar in normal and OA osteoblasts, whereas the expression and production of Rspo-2 were reduced in OA osteoblasts due to elevated levels of transforming growth factor β1 in these cells. The reduced Wnt-3a–dependent TOPflash TCF/LEF luciferase reporter activity in OA osteoblasts as compared to normal osteoblasts was corrected by the addition of recombinant human Rspo-2. Wnt-3a–dependent β-catenin levels were also corrected in OA osteoblasts by Rspo-2 addition. Wnt-3a alone increased the mineralization of OA osteoblasts, which was further increased by Rspo-2.
Reduced Rspo-2 levels in OA osteoblasts are responsible, at least in part, for their reduced Wnt/β-catenin signaling and abnormal mineralization. As Rspo-2 is a secreted soluble protein, this could lead to potential new avenues of treatment of OA.