Mutation of Results in Reduced Cartilage Markers in a Zebrafish Model of Otosclerosis.

Bone diseases such as otosclerosis (conductive hearing loss) and osteoporosis (low bone mineral density) can result from the abnormal expression of genes that regulate cartilage and bone development. The forkhead box transcription factor has been identified as the causative gene in a family with autosomal dominant otosclerosis and has been reported as a candidate gene in GWAS meta-analyses for osteoporosis. This potentially indicates a novel role for in chondrogenesis, osteogenesis, and bone remodelling. We created a mutant zebrafish strain as a model for otosclerosis and osteoporosis and examined jaw bones that are homologous to the mammalian middle ear bones, and mineralization of the axial skeleton. We demonstrate that regulates the expression of collagen genes such as and , and results in a delay in jawbone mineralization, while the axial skeleton remains unchanged. may also act with other forkhead genes such as , as loss of in a mutant background increases the severity of jaw calcification phenotypes when compared to each mutant alone. Our zebrafish model demonstrates atypical cartilage formation and mineralization in the zebrafish craniofacial skeleton in mutants and demonstrates that aberrant collagen expression may underlie the development of otosclerosis.