# WISP3 and Progressive Pseudorheumatoid Arthropathy of Childhood

> **NIH NIH R56** · BOSTON CHILDREN'S HOSPITAL · 2024 · $122,284

## Abstract

Novel strategies are needed when standard approaches fail to delineate mechanisms by which mutations
cause disease. This is the case for Progressive Pseudorheumatoid Arthropathy of Childhood (PPAC), a
degenerative joint disease caused by genetic deficiency of Wnt-inducible signaling pathway protein 3 (WISP3,
also known as CCN6). Patients appear normal at birth, but during childhood develop painful, polyarticular,
degenerative joint disease. In teenage years patients require hip and knee arthroplasties, and they have joints
that resemble end-stage osteoarthritis. Because it is unethical to obtain prospective cartilage biopsies from
children, an animal model is needed to understand the pathobiology that underlies PPAC. Wisp3 knockout
mice did not model PPAC. Therefore, we knocked out WISP3 in sheep, which are larger and longer-lived
animals and have cartilage that is more similar to human cartilage than mice. Like patients with PPAC, our KO
sheep appeared clinically normal at birth but developed altered gaits and joint tenderness with movement and
palpation by 5 months of age. Now that we have an animal model of PPAC, we propose to expand our flock
of KO sheep and prospectively evaluate them clinically, radiographically, histologically, transcriptomically,
Raman spectroscopically, biomechanically and biochemically. We will couple these studies with histologic
and transcriptomic data we obtain from articular-like cartilage tissues that we differentiate from PPAC patient-
derived induced pluripotent stem cells (iPSCs). We previously studied 2 isogenic pairs of WISP3-deficient
and WISP3-sufficient human PSCs, and observed WISP3 deficiency altered several biologically plausible
pathways involved in chondrocyte differentiation and cartilage homeostasis. We now want to determine if
these differences can be strengthened and refined by including 3 new PPAC patient-derived iPSC lines
and their isogenic controls. Pathways suggested by iPSC studies can be tested in KO sheep, and data
from KO sheep can be compared to that obtained from iPSCs. Successful completion of our sheep
experiments will provide insights into the genes and pathways that are altered by WISP3-deficiency in
vivo. Successful completion of our iPSC experiments will inform us about the utility of using patient iPSC-
derived articular-like cartilage tissue to model in vitro that which occurs in articular cartilage in vivo.
Together, these complementary approaches will provide important information about the function of WISP3
in cartilage. The KO sheep and the patient-derived iPSCs also can serve as preclinical models for testing
therapies to benefit patients with PPAC and, perhaps, be used to identify new approaches for protecting
cartilage from common degenerative joint disorders.

## Key facts

- **NIH application ID:** 11175145
- **Project number:** 1R56AR084685-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** April Marie Craft
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $122,284
- **Award type:** 1
- **Project period:** 2024-09-16 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175145

## Citation

> US National Institutes of Health, RePORTER application 11175145, WISP3 and Progressive Pseudorheumatoid Arthropathy of Childhood (1R56AR084685-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11175145. Licensed CC0.

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