The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling

Abstract

In humans, loss-of-function mutations in the gene encoding Wnt1 inducible signaling pathway protein 3 (WISP3) cause the autosomal-recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD). However, in mice there is no apparent phenotype caused by Wisp3 deficiency or overexpression. Consequently, the in vivo activities of Wisp3 have remained elusive. We cloned the zebrafish ortholog of Wisp3 and investigated its biologic activity in vivo using gain-of-function and loss-of-function approaches. Overexpression of zebrafish Wisp3 protein inhibited bone morphogenetic protein (BMP) and Wnt signaling in developing zebrafish. Conditioned medium-containing zebrafish and human Wisp3 also inhibited BMP and Wnt signaling in mammalian cells by binding to BMP ligand and to the Wnt coreceptors low-density lipoprotein receptor-related protein 6 (LRP6) and Frizzled, respectively. Wisp3 proteins containing disease-causing amino acid substitutions found in patients with PPD had reduced activity in these assays. Morpholino-mediated inhibition of zebrafish Wisp3 protein expression in developing zebrafish affected pharyngeal cartilage size and shape. These data provide a biologic assay for Wisp3, reveal a role for Wisp3 during zebrafish cartilage development, and suggest that dysregulation of BMP and/or Wnt signaling contributes to cartilage failure in humans with PPD.

Patients with progressive pseudorheumatoid dysplasia: From clinical diagnosis to molecular studies

“…Therefore, any depletion or dysfunction of WISP3 may result in a loss of WISP3 protein function, which apparently interferes with normal postnatal growth and cartilage homeostasis, leading to joint degeneration (5,8,15,16). The mutation analysis of the WISP3 gene may confirm the original diagnosis of PPD based on clinical manifestations and imaging analysis.…”

Progressive Pseudorheumatoid Condrodysplasia, an Unusual Cause of Joint Swelling and Stiffness

“…The WISP3 gene is a member of the connective tissue growth factor gene family and encodes a secreted cysteine-rich protein expressed by synoviocytes and chondrocytes (3). These proteins have roles in cell growth, differentiation and are essential for normal postnatal skeletal growth and cartilage homeostasis.…”

A genotyping assay for missense mutation in WISP3 gene associated with childhood onset pseudorheumatoid arthropathy

“…It has been observed previously that reduction or loss of function of WISP3 increase the amount of cellular reactive oxygen species (ROS) in human chondrocyte cell line (5). So far it is known that WISP3 promotes superoxide dismutase (SOD) expression and activity in chondrocytes (6). SOD act as an antioxidant that control the accumulation of ROS thus preventing a destructive impact of ROS to proteins, DNA, lipids, and carbohydrates in cell under stress conditions.…”