A Zebrafish Mutant in the Extracellular Matrix Protein Gene efemp1 as a Model for Spinal Osteoarthritis.

Simple Summary: Osteoarthritis is a debilitating and painful joint disease affecting mainly aging animals and people. Previous results indicated that Efemp1, a protein present in the extracellular matrix that surrounds each cell, is increased in the blood, urine, and bone of osteoarthritic patients. We used the zebrafish as a model system to investigate the role of the Efemp1 protein in skeletal development and homeostasis. We showed that the efemp1 gene is expressed in the brain, the pharyngeal cartilage, and the developing notochord which will later form the vertebral column. We generated a mutant in this gene, devoid of a functional Efemp1 protein, to show that this mutant presents transient deformities in its head cartilage at early stages. More importantly, adult mutants expressed a phenotype characterized by a smaller distance between vertebrae and ruffled edges (bone spurs) at the vertebral ends. This defect is reminiscent of that observed in spinal osteoarthritis; we therefore propose the efemp1−/− mutant line as the first zebrafish model to study this condition. Osteoarthritis is a degenerative articular disease affecting mainly aging animals and people. The extracellular matrix protein Efemp1 was previously shown to have higher turn-over and increased secretion in the blood serum, urine, and subchondral bone of knee joints in osteoarthritic patients. Here, we use the zebrafish as a model system to investigate the function of Efemp1 in vertebrate skeletal development and homeostasis. Using in situ hybridization, we show that the efemp1 gene is expressed in the brain, the pharyngeal arches, and in the chordoblasts surrounding the notochord at 48 hours post-fertilization. We generated an efemp1 mutant line, using the CRISPR/Cas9 method, that produces a severely truncated Efemp1 protein. These mutant larvae presented a medially narrower chondrocranium at 5 days, which normalized later at day 10. At age 1.5 years, µCT analysis revealed an increased tissue mineral density and thickness of the vertebral bodies, as well as a decreased distance between individual vertebrae and ruffled borders of the vertebral centra. This novel defect, which has, to our knowledge, never been described before, suggests that the efemp1 mutant represents the first zebrafish model for spinal osteoarthritis. [ABSTRACT FROM AUTHOR]