Progressive pseudorheumatoid dysplasia (PPD), which causes joint failure in early adulthood, results from genetic mutations in the WISP3 gene that lead to the generation of nonfunctional WISP3 protein.
Understanding why WISP3 deficiency causes PPD has been difficult because mice lacking WISP3 have no apparent symptoms. In a new study, Matthew Warman and colleagues from Case Western Reserve University, Cleveland, provide insight into the functions of WISP3 by studying its function in zebrafish.
It was shown that overexpression of WISP3 in zebrafish inhibited signaling through two proteins -- BMP and Wnt. Zebrafish and human WISP3 were also shown to inhibit BMP and Wnt signaling in mammalian cells.
Importantly, WISP3 resembling that found in individuals with PPD was not as effective at inhibiting BMP and Wnt signaling.
As cartilage development in zebrafish in which WISP3 expression was eliminated was defective, the authors conclude that dysregulated BMP and/or Wnt signaling contributes to the cartilage defects, and thereby joint failure, observed in individuals with PPD.
Article: The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling, The Journal of Clinical Investigation
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