Modeling Progressive Pseudorheumatoid Arthropathy of Childhood: Disease Progression and Cartilage Pathology in CCN6 Knockout Sheep.

OBJECTIVE

Progressive Pseudorheumatoid Arthropathy of Childhood (PPAC), also known as Progressive Pseudorheumatoid Dysplasia (PPRD), is an autosomal recessive disorder caused by loss-of-function variants in Cellular Communication Network Factor 6 (CCN6, aka, WISP3). Patients with PPAC are asymptomatic at birth but develop polyarticular arthropathy in childhood, requiring multiple arthroplasties before 30 years of age. Currently, no therapy prevents or delays PPAC progression. Furthermore, how loss of CCN6 affects joint development or homeostasis is unknown due to the unavailability of pre-symptomatic patient tissue and the absence of a phenotype in Ccn6 knockout (KO) mice.

METHODS

CCN6-KO sheep were generated, anticipating that a larger and longer-lived animal would better model human PPAC.

RESULTS

Juvenile KO sheep developed clinical signs of joint disease that worsened with age, and histologic examination of KO tissue revealed precocious cartilage damage. Additionally, KO cartilage differed from WT biomechanically, biochemically, and transcriptomically; with KO sheep cartilage sharing multiple transcriptomic features observed in cartilage derived from PPAC patient-induced pluripotent cell lines.

CONCLUSION

These data indicate CCN6-KO sheep recapitulate clinical, histological, and molecular features of PPAC, and can be used to elucidate disease mechanisms and test therapies.