Cartilage and bone disease in a mouse model of Farber lipogranulomatosis and response to treatment

Farber lipogranulomatosis (Farber disease, FD) is the lysosomal disorder due to the deficiency of acid ceramidase (AC) and the resultant accumulation of the sphingolipid, ceramide. Ceramide-driven inflammation is characteristic of the disease, resulting in massive macrophage infiltration into many tissues. Cartilage sites are particularly susceptible to this inflammatory process, resulting in homing of macrophages and nodule formation at these sites. A mouse model of severe Farber disease (asah1-/- mice) has been constructed (Alayoubi et al., 2013) and used to investigate the pathophysiology of the disease and approaches to treatment. Affected animals are particularly small, exhibit failure to thrive, and survive only 8-12 weeks. In this study we examined the bones and cartilage of these mice and the potential of enzyme replacement therapy (ERT) to recover the phenotype. Cultured chondrocytes from asah1-/- mice exhibited massive ceramide storage and extremely poor growth. qPCR analysis of several chondrogenic genes (collagen 2, aggrecan, Sox-9) revealed very low expression, suggesting a defect in chondrogenesis. Treatment of the asah1-/- chondrocytes with recombinant human AC (rhAC) recovered much of the growth and chondrogenic defects. Histological and imaging assessments of the bones and cartilage of untreated asah1-/- mice revealed lipid-filled storage cells, disorganized bone growth plates, and defective articular cartilage. Subcutaneous nodules were not found, although clusters of macrophages were evident. Treatment of asah1-/- mice with rhAC beginning in the first week of life markedly reduced inflammation, prevented ceramide storage in most organs, and modestly extended lifespan. The effect of enzyme treatment on the cartilage and bones is under investigation.